230 results on '"Bottaro, Sandro"'
Search Results
2. Discovering functionally important sites in proteins
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Cagiada, Matteo, Bottaro, Sandro, Lindemose, Søren, Schenstrøm, Signe M., Stein, Amelie, Hartmann-Petersen, Rasmus, and Lindorff-Larsen, Kresten
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- 2023
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3. How to learn from inconsistencies: Integrating molecular simulations with experimental data
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Orioli, Simone, Larsen, Andreas Haahr, Bottaro, Sandro, and Lindorff-Larsen, Kresten
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Physics - Chemical Physics ,Physics - Biological Physics - Abstract
Molecular simulations and biophysical experiments can be used to provide independent and complementary insights into the molecular origin of biological processes. A particularly useful strategy is to use molecular simulations as a modelling tool to interpret experimental measurements, and to use experimental data to refine our biophysical models. Thus, explicit integration and synergy between molecular simulations and experiments is fundamental for furthering our understanding of biological processes. This is especially true in the case where discrepancies between measured and simulated observables emerge. In this chapter, we provide an overview of some of the core ideas behind methods that were developed to improve the consistency between experimental information and numerical predictions. We distinguish between situations where experiments are used to refine our understanding and models of specific systems, and situations where experiments are used more generally to refine transferable models. We discuss different philosophies and attempt to unify them in a single framework. Until now, such integration between experiments and simulations have mostly been applied to equilibrium data, and we discuss more recent developments aimed to analyse time-dependent or time-resolved data., Comment: 67 pages, 4 figures, 206 references, revised version
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- 2019
4. Promoting transparency and reproducibility in enhanced molecular simulations
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Bonomi, Massimiliano, Bussi, Giovanni, Camilloni, Carlo, Tribello, Gareth A, Banáš, Pavel, Barducci, Alessandro, Bernetti, Mattia, Bolhuis, Peter G, Bottaro, Sandro, Branduardi, Davide, Capelli, Riccardo, Carloni, Paolo, Ceriotti, Michele, Cesari, Andrea, Chen, Haochuan, Chen, Wei, Colizzi, Francesco, De, Sandip, De La Pierre, Marco, Donadio, Davide, Drobot, Viktor, Ensing, Bernd, Ferguson, Andrew L, Filizola, Marta, Fraser, James S, Fu, Haohao, Gasparotto, Piero, Gervasio, Francesco Luigi, Giberti, Federico, Gil-Ley, Alejandro, Giorgino, Toni, Heller, Gabriella T, Hocky, Glen M, Iannuzzi, Marcella, Invernizzi, Michele, Jelfs, Kim E, Jussupow, Alexander, Kirilin, Evgeny, Laio, Alessandro, Limongelli, Vittorio, Lindorff-Larsen, Kresten, Löhr, Thomas, Marinelli, Fabrizio, Martin-Samos, Layla, Masetti, Matteo, Meyer, Ralf, Michaelides, Angelos, Molteni, Carla, Morishita, Tetsuya, Nava, Marco, Paissoni, Cristina, Papaleo, Elena, Parrinello, Michele, Pfaendtner, Jim, Piaggi, Pablo, Piccini, GiovanniMaria, Pietropaolo, Adriana, Pietrucci, Fabio, Pipolo, Silvio, Provasi, Davide, Quigley, David, Raiteri, Paolo, Raniolo, Stefano, Rydzewski, Jakub, Salvalaglio, Matteo, Sosso, Gabriele Cesare, Spiwok, Vojtěch, Šponer, Jiří, Swenson, David WH, Tiwary, Pratyush, Valsson, Omar, Vendruscolo, Michele, Voth, Gregory A, and White, Andrew
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Biological Sciences ,Humans ,Models ,Molecular ,Molecular Conformation ,Molecular Dynamics Simulation ,Reproducibility of Results ,Software ,PLUMED consortium ,Technology ,Medical and Health Sciences ,Developmental Biology ,Biological sciences - Abstract
The PLUMED consortium unifies developers and contributors to PLUMED, an open-source library for enhanced-sampling, free-energy calculations and the analysis of molecular dynamics simulations. Here, we outline our efforts to promote transparency and reproducibility by disseminating protocols for enhanced-sampling molecular simulations.
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- 2019
5. A nucleobase-centered coarse-grained representation for structure prediction of RNA motifs
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Poblete, Simón, Bottaro, Sandro, and Bussi, Giovanni
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Quantitative Biology - Biomolecules ,Physics - Biological Physics ,Physics - Chemical Physics - Abstract
We introduce the SPlit-and-conQueR (SPQR) model, a coarse-grained representation of RNA designed for structure prediction and refinement. In our approach, the representation of a nucleotide consists of a point particle for the phosphate group and an anisotropic particle for the nucleoside. The interactions are, in principle, knowledge-based potentials inspired by the ESCORE function, a base-centered scoring function. However, a special treatment is given to base-pairing interactions and certain geometrical conformations which are lost in a raw knowledge-base model. This results in a representation able to describe planar canonical and non-canonical base pairs and base-phosphate interactions and to distinguish sugar puckers and glycosidic torsion conformations. The model is applied to the folding of several structures, including duplexes with internal loops of non-canonical base pairs, tetraloops, junctions and a pseudoknot. For the majority of these systems, experimental structures are correctly predicted at the level of individual contacts. We also propose a method for efficiently reintroducing atomistic detail from the coarse-grained representation., Comment: Accepted for publication on Nucleic Acids Research
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- 2017
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6. Effects and limitations of a nucleobase-driven backmapping procedure for nucleic acids using steered Molecular Dynamics
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Poblete, Simón, Bottaro, Sandro, and Bussi, Giovanni
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Physics - Biological Physics ,Physics - Computational Physics ,Quantitative Biology - Biomolecules - Abstract
Coarse-grained models can be of great help to address the problem of structure prediction in nucleic acids. On one hand they can make the prediction more efficient, while on the other hand, they can also help to identify the essential degrees of freedom and interactions for the description of a number of structures. With the aim to provide an all-atom representation in an explicit solvent to the predictions of our SPlit and conQueR (SPQR) coarse-grained model of RNA, we recently introduced a backmapping procedure which enforces the predicted structure into an atomistic one by means of steered Molecular Dynamics. These simulations minimize the ERMSD, a particular metric which deals exclusively with the relative arrangement of nucleobases, between the atomistic representation and the target structure. In this paper, we explore the effects of this approach on the resulting interaction networks and backbone conformations by applying it on a set of fragments using as a target their native structure. We find that the geometry of the target structures can be reliably recovered, with limitations in the regions with unpaired bases such as bulges. In addition, we observe that the folding pathway can also change depending on the parameters used in the definition of the ERMSD and the use of other metrics such as the RMSD., Comment: Submitted
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- 2017
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7. The 5′-terminal stem–loop RNA element of SARS-CoV-2 features highly dynamic structural elements that are sensitive to differences in cellular pH
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Toews, Sabrina, primary, Wacker, Anna, additional, Faison, Edgar M, additional, Duchardt-Ferner, Elke, additional, Richter, Christian, additional, Mathieu, Daniel, additional, Bottaro, Sandro, additional, Zhang, Qi, additional, and Schwalbe, Harald, additional
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- 2024
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8. Computer Folding of RNA Tetraloops: Identification of Key Force Field Deficiencies
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Kührová, Petra, Best, Robert B., Bottaro, Sandro, Bussi, Giovanni, Šponer, Jiří, Otyepka, Michal, and Banáš, Pavel
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Quantitative Biology - Biomolecules ,Physics - Biological Physics ,Physics - Chemical Physics ,Physics - Computational Physics - Abstract
The computer-aided folding of biomolecules, particularly RNAs, is one of the most difficult challenges in computational structural biology. RNA tetraloops are fundamental RNA motifs playing key roles in RNA folding and RNA-RNA and RNA-protein interactions. Although state-of-the-art Molecular Dynamics (MD) force fields correctly describe the native state of these tetraloops as a stable free-energy basin on the microsecond time scale, enhanced sampling techniques reveal that the native state is not the global free energy minimum, suggesting yet unidentified significant imbalances in the force fields. Here, we tested our ability to fold the RNA tetraloops in various force fields and simulation settings. We employed three different enhanced sampling techniques, namely, temperature replica exchange MD (T-REMD), replica exchange with solute tempering (REST2), and well-tempered metadynamics (WT-MetaD). We aimed to separate problems caused by limited sampling from those due to force-field inaccuracies. We found that none of the contemporary force fields is able to correctly describe folding of the 5'-GAGA-3' tetraloop over a range of simulation conditions. We thus aimed to identify which terms of the force field are responsible for this poor description of TL folding. We showed that at least two different imbalances contribute to this behavior, namely, overstabilization of base-phosphate and/or sugar-phosphate interactions and underestimated stability of the hydrogen bonding interaction in base pairing. The first artifact stabilizes the unfolded ensemble, while the second one destabilizes the folded state. The former problem might be partially alleviated by reparametrization of the van der Waals parameters of the phosphate oxygens suggested by Case et al., while in order to overcome the latter effect we suggest local potentials to better capture hydrogen bonding interactions., Comment: Reprinted with permission from J. Chem. Theory Comput. 2016, 12 (9), pp 4534-4548. Copyright 2016 American Chemical Society
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- 2016
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9. Free Energy Landscape of GAGA and UUCG RNA Tetraloops
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Bottaro, Sandro, Banáš, Pavel, Sponer, Jiri, and Bussi, Giovanni
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Quantitative Biology - Biomolecules ,Physics - Biological Physics ,Physics - Chemical Physics ,Physics - Computational Physics - Abstract
We report the folding thermodynamics of ccUUCGgg and ccGAGAgg RNA tetraloops using atomistic molecular dynamics simulations. We obtain a previously unreported estimation of the folding free energy using parallel tempering in combination with well-tempered metadynamics. A key ingredient is the use of a recently developed metric distance, eRMSD, as a biased collective variable. We find that the native fold of both tetraloops is not the global free energy minimum using the Amber\c{hi}OL3 force field. The estimated folding free energies are 30.2kJ/mol for UUCG and 7.5 kJ/mol for GAGA, in striking disagreement with experimental data. We evaluate the viability of all possible one-dimensional backbone force field corrections. We find that disfavoring the gauche+ region of {\alpha} and {\zeta} angles consistently improves the existing force field. The level of accuracy achieved with these corrections, however, cannot be considered sufficient by judging on the basis of available thermodynamic data and solution experiments., Comment: Journal of Physical Chemistry Letters (2016)
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- 2016
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10. Empirical corrections to the Amber RNA force field with Target Metadynamics
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Gil-Ley, Alejandro, Bottaro, Sandro, and Bussi, Giovanni
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Quantitative Biology - Biomolecules ,Condensed Matter - Statistical Mechanics ,Physics - Biological Physics ,Physics - Chemical Physics ,Physics - Computational Physics - Abstract
The computational study of conformational transitions in nucleic acids still faces many challenges. For example, in the case of single stranded RNA tetranucleotides, agreement between simulations and experiments is not satisfactory due to inaccuracies in the force fields commonly used in molecular dynamics simulations. We here use experimental data collected from high-resolution X-ray structures to attempt an improvement of the latest version of the AMBER force field. A modified metadynamics algorithm is used to calculate correcting potentials designed to enforce experimental distributions of backbone torsion angles. Replica-exchange simulations of tetranucleotides including these correcting potentials show significantly better agreement with independent solution experiments for the oligonucleotides containing pyrimidine bases. Although the proposed corrections do not seem to be portable to generic RNA systems, the simulations revealed the importance of the alpha and beta backbone angles on the modulation of the RNA conformational ensemble. The correction protocol presented here suggests a systematic procedure for force-field refinement.
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- 2016
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11. RNA Folding Pathways in Stop Motion
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Bottaro, Sandro, Gil-Ley, Alejandro, and Bussi, Giovanni
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Quantitative Biology - Biomolecules ,Physics - Biological Physics ,Physics - Chemical Physics ,Physics - Computational Physics - Abstract
We introduce a method for predicting RNA folding pathways, with an application to the most important RNA tetraloops. The method is based on the idea that ensembles of three-dimensional fragments extracted from high-resolution crystal structures are heterogeneous enough to describe metastable as well as intermediate states. These ensembles are first validated by performing a quantitative comparison against available solution NMR data of a set of RNA tetranucleotides. Notably, the agreement is better with respect to the one obtained by comparing NMR with extensive all-atom molecular dynamics simulations. We then propose a procedure based on diffusion maps and Markov models that makes it possible to obtain reaction pathways and their relative probabilities from fragment ensembles. This approach is applied to study the helix-to-loop folding pathway of all the tetraloops from the GNRA and UNCG families. The results give detailed insights into the folding mechanism that are compatible with available experimental data and clarify the role of intermediate states observed in previous simulation studies. The method is computationally inexpensive and can be used to study arbitrary conformational transitions., Comment: Accepted for publication on Nucleic Acids Research
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- 2016
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12. Elastic network models for RNA: a comparative assessment with molecular dynamics and SHAPE experiments
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Pinamonti, Giovanni, Bottaro, Sandro, Micheletti, Cristian, and Bussi, Giovanni
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Quantitative Biology - Biomolecules ,Condensed Matter - Statistical Mechanics ,Physics - Biological Physics ,Physics - Chemical Physics - Abstract
Elastic network models (ENMs) are valuable and efficient tools for characterizing the collective internal dynamics of proteins based on the knowledge of their native structures. The increasing evidence that the biological functionality of RNAs is often linked to their innate internal motions, poses the question of whether ENM approaches can be successfully extended to this class of biomolecules. This issue is tackled here by considering various families of elastic networks of increasing complexity applied to a representative set of RNAs. The fluctuations predicted by the alternative ENMs are stringently validated by comparison against extensive molecular dynamics simulations and SHAPE experiments. We find that simulations and experimental data are systematically best reproduced by either an all-atom or a three-beads-per-nucleotide representation (sugar-base-phosphate), with the latter arguably providing the best balance of accuracy and computational complexity., Comment: This article has been accepted for publication in Nucleic Acids Research Published by Oxford University Press
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- 2015
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13. Kissing loop interaction in adenine riboswitch: insights from umbrella sampling simulations
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Di Palma, Francesco, Bottaro, Sandro, and Bussi, Giovanni
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Quantitative Biology - Biomolecules ,Physics - Biological Physics ,Physics - Chemical Physics - Abstract
Riboswitches are cis-acting regulatory RNA elements prevalently located in the leader sequences of bacterial mRNA. An adenine sensing riboswitch cis-regulates adeninosine deaminase gene (add) in Vibrio vulnificus. The structural mechanism regulating its conformational changes upon ligand binding mostly remains to be elucidated. In this open framework it has been suggested that the ligand stabilizes the interaction of the distal "kissing loop" complex. Using accurate full-atom molecular dynamics with explicit solvent in combination with enhanced sampling techniques and advanced analysis methods it could be possible to provide a more detailed perspective on the formation of these tertiary contacts. In this work, we used umbrella sampling simulations to study the thermodynamics of the kissing loop complex in the presence and in the absence of the cognate ligand. We enforced the breaking/formation of the loop-loop interaction restraining the distance between the two loops. We also assessed the convergence of the results by using two alternative initialization protocols. A structural analysis was performed using a novel approach to analyze base contacts. Our simulations qualitatively indicated that the ligand could stabilize the kissing loop complex. We also compared with previously published simulation studies. Kissing complex stabilization given by the ligand was compatible with available experimental data. However, the dependence of its value on the initialization protocol of the umbrella sampling simulations posed some questions on the quantitative interpretation of the results and called for better converged enhanced sampling simulations., Comment: Accepted for publication on BMC Bioinformatics
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- 2015
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14. Towards de novo RNA 3D structure prediction
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Bottaro, Sandro, Di Palma, Francesco, and Bussi, Giovanni
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Quantitative Biology - Biomolecules ,Physics - Biological Physics ,Physics - Chemical Physics ,Physics - Computational Physics - Abstract
RNA is a fundamental class of biomolecules that mediate a large variety of molecular processes within the cell. Computational algorithms can be of great help in the understanding of RNA structure-function relationship. One of the main challenges in this field is the development of structure-prediction algorithms, which aim at the prediction of the three-dimensional (3D) native fold from the sole knowledge of the sequence. In a recent paper, we have introduced a scoring function for RNA structure prediction. Here, we analyze in detail the performance of the method, we underline strengths and shortcomings, and we discuss the results with respect to state-of-the-art techniques. These observations provide a starting point for improving current methodologies, thus paving the way to the advances of more accurate approaches for RNA 3D structure prediction., Comment: Accepted for publication on RNA & Disease
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- 2015
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15. Accurate multiple time step in biased molecular simulations
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Ferrarotti, Marco Jacopo, Bottaro, Sandro, Pérez-Villa, Andrea, and Bussi, Giovanni
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Physics - Computational Physics ,Condensed Matter - Statistical Mechanics ,Physics - Biological Physics ,Physics - Chemical Physics - Abstract
Many recently introduced enhanced sampling techniques are based on biasing coarse descriptors (collective variables) of a molecular system on the fly. Sometimes the calculation of such collective variables is expensive and becomes a bottleneck in molecular dynamics simulations. An algorithm to treat smooth biasing forces within a multiple time step framework is here discussed. The implementation is simple and allows a speed up when expensive collective variables are employed. The gain can be substantial when using massively parallel or GPU-based molecular dynamics software. Moreover, a theoretical framework to assess the sampling accuracy is introduced, which can be used to assess the choice of the integration time step in both single and multiple time step biased simulations., Comment: Accepted for publication on J. Chem. Theory Comput
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- 2014
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16. The Role of Nucleobase Interactions in RNA Structure and Dynamics
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Bottaro, Sandro, Di Palma, Francesco, and Bussi, Giovanni
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Quantitative Biology - Biomolecules ,Physics - Biological Physics ,Physics - Chemical Physics ,Physics - Computational Physics - Abstract
The intricate network of interactions observed in RNA three-dimensional structures is often described in terms of a multitude of geometrical properties, including helical parameters, base pairing/stacking, hydrogen bonding and backbone conformation. We show that a simple molecular representation consisting in one oriented bead per nucleotide can account for the fundamental structural properties of RNA. In this framework, canonical Watson-Crick, non-Watson-Crick base-pairing and base-stacking interactions can be unambiguously identified within a well-defined interaction shell. We validate this representation by performing two independent, complementary tests. First, we use it to construct a sequence-independent, knowledge-based scoring function for RNA structural prediction, which compares favorably to fully atomistic, state-of-the-art techniques. Second, we define a metric to measure deviation between RNA structures that directly reports on the differences in the base-base interaction network. The effectiveness of this metric is tested with respect to the ability to discriminate between structurally and kinetically distant RNA conformations, performing better compared to standard techniques. Taken together, our results suggest that this minimalist, nucleobase-centric representation captures the main interactions that are relevant for describing RNA structure and dynamics., Comment: Accepted for publication on Nucleic Acids Research
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- 2014
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17. Potentials of Mean Force for Protein Structure Prediction Vindicated, Formalized and Generalized
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Hamelryck, Thomas, Borg, Mikael, Paluszewski, Martin, Paulsen, Jonas, Frellsen, Jes, Andreetta, Christian, Boomsma, Wouter, Bottaro, Sandro, and Ferkinghoff-Borg, Jesper
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Quantitative Biology - Biomolecules ,Condensed Matter - Statistical Mechanics - Abstract
Understanding protein structure is of crucial importance in science, medicine and biotechnology. For about two decades, knowledge based potentials based on pairwise distances -- so-called "potentials of mean force" (PMFs) -- have been center stage in the prediction and design of protein structure and the simulation of protein folding. However, the validity, scope and limitations of these potentials are still vigorously debated and disputed, and the optimal choice of the reference state -- a necessary component of these potentials -- is an unsolved problem. PMFs are loosely justified by analogy to the reversible work theorem in statistical physics, or by a statistical argument based on a likelihood function. Both justifications are insightful but leave many questions unanswered. Here, we show for the first time that PMFs can be seen as approximations to quantities that do have a rigorous probabilistic justification: they naturally arise when probability distributions over different features of proteins need to be combined. We call these quantities reference ratio distributions deriving from the application of the reference ratio method. This new view is not only of theoretical relevance, but leads to many insights that are of direct practical use: the reference state is uniquely defined and does not require external physical insights; the approach can be generalized beyond pairwise distances to arbitrary features of protein structure; and it becomes clear for which purposes the use of these quantities is justified. We illustrate these insights with two applications, involving the radius of gyration and hydrogen bonding. In the latter case, we also show how the reference ratio method can be iteratively applied to sculpt an energy funnel. Our results considerably increase the understanding and scope of energy functions derived from known biomolecular structures.
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- 2010
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18. Biophysical experiments and biomolecular simulations : A perfect match?
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Bottaro, Sandro and Lindorff-Larsen, Kresten
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- 2018
19. Effects and limitations of a nucleobase-driven backmapping procedure for nucleic acids using steered molecular dynamics
- Author
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Poblete, Simón, Bottaro, Sandro, and Bussi, Giovanni
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- 2018
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20. Mapping the Universe of RNA Tetraloop Folds
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Bottaro, Sandro and Lindorff-Larsen, Kresten
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- 2017
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21. How to learn from inconsistencies: Integrating molecular simulations with experimental data
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Orioli, Simone, primary, Larsen, Andreas Haahr, additional, Bottaro, Sandro, additional, and Lindorff-Larsen, Kresten, additional
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- 2020
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22. Integrating Molecular Simulation and Experimental Data: A Bayesian/Maximum Entropy Reweighting Approach
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Bottaro, Sandro, primary, Bengtsen, Tone, additional, and Lindorff-Larsen, Kresten, additional
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- 2020
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23. Integrated NMR/Molecular Dynamics Determination of the Ensemble Conformation of a Thermodynamically Stable CUUG RNA Tetraloop
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Oxenfarth, Andreas, primary, Kümmerer, Felix, additional, Bottaro, Sandro, additional, Schnieders, Robbin, additional, Pinter, György, additional, Jonker, Hendrik R. A., additional, Fürtig, Boris, additional, Richter, Christian, additional, Blackledge, Martin, additional, Lindorff-Larsen, Kresten, additional, and Schwalbe, Harald, additional
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- 2023
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24. Integrated NMR/Molecular Dynamics Determination of the Ensemble Conformation of a Thermodynamically Stable CUUG RNA Tetraloop
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Oxenfarth, Andreas, Kümmerer, Felix, Bottaro, Sandro, Schnieders, Robbin, Pinter, György, Jonker, Hendrik R.A., Fürtig, Boris, Richter, Christian, Blackledge, Martin, Lindorff-Larsen, Kresten, Schwalbe, Harald, Oxenfarth, Andreas, Kümmerer, Felix, Bottaro, Sandro, Schnieders, Robbin, Pinter, György, Jonker, Hendrik R.A., Fürtig, Boris, Richter, Christian, Blackledge, Martin, Lindorff-Larsen, Kresten, and Schwalbe, Harald
- Abstract
Both experimental and theoretical structure determinations of RNAs have remained challenging due to the intrinsic dynamics of RNAs. We report here an integrated nuclear magnetic resonance/molecular dynamics (NMR/MD) structure determination approach to describe the dynamic structure of the CUUG tetraloop. We show that the tetraloop undergoes substantial dynamics, leading to averaging of the experimental data. These dynamics are particularly linked to the temperature-dependent presence of a hydrogen bond within the tetraloop. Interpreting the NMR data by a single structure represents the low-temperature structure well but fails to capture all conformational states occurring at a higher temperature. We integrate MD simulations, starting from structures of CUUG tetraloops within the Protein Data Bank, with an extensive set of NMR data, and provide a structural ensemble that describes the dynamic nature of the tetraloop and the experimental NMR data well. We thus show that one of the most stable and frequently found RNA tetraloops displays substantial dynamics, warranting such an integrated structural approach., Both experimental and theoretical structure determinations of RNAs have remained challenging due to the intrinsic dynamics of RNAs. We report here an integrated nuclear magnetic resonance/molecular dynamics (NMR/MD) structure determination approach to describe the dynamic structure of the CUUG tetraloop. We show that the tetraloop undergoes substantial dynamics, leading to averaging of the experimental data. These dynamics are particularly linked to the temperature-dependent presence of a hydrogen bond within the tetraloop. Interpreting the NMR data by a single structure represents the low-temperature structure well but fails to capture all conformational states occurring at a higher temperature. We integrate MD simulations, starting from structures of CUUG tetraloops within the Protein Data Bank, with an extensive set of NMR data, and provide a structural ensemble that describes the dynamic nature of the tetraloop and the experimental NMR data well. We thus show that one of the most stable and frequently found RNA tetraloops displays substantial dynamics, warranting such an integrated structural approach.
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- 2023
25. Hepatitis C virus RNA is 5'-capped with flavin adenine dinucleotide
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Sherwood, Anna V, Rivera-Rangel, Lizandro R, Ryberg, Line A, Larsen, Helena S, Anker, Klara M, Costa, Rui, Vågbø, Cathrine B, Jakljevič, Eva, Pham, Long V, Fernandez-Antunez, Carlota, Indrisiunaite, Gabriele, Podolska-Charlery, Agnieszka, Grothen, Julius E R, Langvad, Nicklas W, Fossat, Nicolas, Offersgaard, Anna, Al-Chaer, Amal, Nielsen, Louise, Kuśnierczyk, Anna, Sølund, Christina, Weis, Nina, Gottwein, Judith M, Holmbeck, Kenn, Bottaro, Sandro, Ramirez, Santseharay, Bukh, Jens, Scheel, Troels K H, Vinther, Jeppe, Sherwood, Anna V, Rivera-Rangel, Lizandro R, Ryberg, Line A, Larsen, Helena S, Anker, Klara M, Costa, Rui, Vågbø, Cathrine B, Jakljevič, Eva, Pham, Long V, Fernandez-Antunez, Carlota, Indrisiunaite, Gabriele, Podolska-Charlery, Agnieszka, Grothen, Julius E R, Langvad, Nicklas W, Fossat, Nicolas, Offersgaard, Anna, Al-Chaer, Amal, Nielsen, Louise, Kuśnierczyk, Anna, Sølund, Christina, Weis, Nina, Gottwein, Judith M, Holmbeck, Kenn, Bottaro, Sandro, Ramirez, Santseharay, Bukh, Jens, Scheel, Troels K H, and Vinther, Jeppe
- Abstract
RNA viruses have evolved elaborate strategies to protect their genomes, including 5' capping. However, until now no RNA 5' cap has been identified for hepatitis C virus 1,2 (HCV), which causes chronic infection, liver cirrhosis and cancer 3. Here we demonstrate that the cellular metabolite flavin adenine dinucleotide (FAD) is used as a non-canonical initiating nucleotide by the viral RNA-dependent RNA polymerase, resulting in a 5'-FAD cap on the HCV RNA. The HCV FAD-capping frequency is around 75%, which is the highest observed for any RNA metabolite cap across all kingdoms of life 4-8. FAD capping is conserved among HCV isolates for the replication-intermediate negative strand and partially for the positive strand. It is also observed in vivo on HCV RNA isolated from patient samples and from the liver and serum of a human liver chimeric mouse model. Furthermore, we show that 5'-FAD capping protects RNA from RIG-I mediated innate immune recognition but does not stabilize the HCV RNA. These results establish capping with cellular metabolites as a novel viral RNA-capping strategy, which could be used by other viruses and affect anti-viral treatment outcomes and persistence of infection.
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- 2023
26. An Efficient Null Model for Conformational Fluctuations in Proteins
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Harder, Tim, Borg, Mikael, Bottaro, Sandro, Boomsma, Wouter, Olsson, Simon, Ferkinghoff-Borg, Jesper, and Hamelryck, Thomas
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- 2012
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27. Discovering functionally important sites in proteins
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Cagiada, Matteo, primary, Bottaro, Sandro, additional, Lindemose, Søren, additional, Schenstrøm, Signe M., additional, Stein, Amelie, additional, Hartmann-Petersen, Rasmus, additional, and Lindorff-Larsen, Kresten, additional
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- 2022
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28. LLM-PBC: Logic Learning Machine-Based Explainable Rules Accurately Stratify the Genetic Risk of Primary Biliary Cholangitis
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Gerussi, A, Verda, D, Cappadona, C, Cristoferi, L, Bernasconi, D, Bottaro, S, Carbone, M, Muselli, M, Invernizzi, P, Asselta, R, Gerussi, Alessio, Verda, Damiano, Cappadona, Claudio, Cristoferi, Laura, Bernasconi, Davide Paolo, Bottaro, Sandro, Carbone, Marco, Muselli, Marco, Invernizzi, Pietro, Asselta, Rosanna, Gerussi, A, Verda, D, Cappadona, C, Cristoferi, L, Bernasconi, D, Bottaro, S, Carbone, M, Muselli, M, Invernizzi, P, Asselta, R, Gerussi, Alessio, Verda, Damiano, Cappadona, Claudio, Cristoferi, Laura, Bernasconi, Davide Paolo, Bottaro, Sandro, Carbone, Marco, Muselli, Marco, Invernizzi, Pietro, and Asselta, Rosanna
- Abstract
Background: The application of Machine Learning (ML) to genetic individual-level data represents a foreseeable advancement for the field, which is still in its infancy. Here, we aimed to evaluate the feasibility and accuracy of an ML-based model for disease risk prediction applied to Primary Biliary Cholangitis (PBC). Methods: Genome-wide significant variants identified in subjects of European ancestry in the recently released second international meta-analysis of GWAS in PBC were used as input data. Quality-checked, individual genomic data from two Italian cohorts were used. The ML included the following steps: import of genotype and phenotype data, genetic variant selection, supervised classification of PBC by genotype, generation of “if-then” rules for disease prediction by logic learning machine (LLM), and model validation in a different cohort. Results: The training cohort included 1345 individuals: 444 were PBC cases and 901 were healthy controls. After pre-processing, 41,899 variants entered the analysis. Several configurations of parameters related to feature selection were simulated. The best LLM model reached an Accuracy of 71.7%, a Matthews correlation coefficient of 0.29, a Youden’s value of 0.21, a Sensitivity of 0.28, a Specificity of 0.93, a Positive Predictive Value of 0.66, and a Negative Predictive Value of 0.72. Thirty-eight rules were generated. The rule with the highest covering (19.14) included the following genes: RIN3, KANSL1, TIMMDC1, TNPO3. The validation cohort included 834 individuals: 255 cases and 579 controls. By applying the ruleset derived in the training cohort, the Area under the Curve of the model was 0.73. Conclusions: This study represents the first illustration of an ML model applied to common variants associated with PBC. Our approach is computationally feasible, leverages individual-level data to generate intelligible rules, and can be used for disease prediction in at-risk individuals.
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- 2022
29. Conformational heterogeneity of UCAAUC RNA oligonucleotide from molecular dynamics simulations, SAXS, and NMR experiments
- Author
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Bergonzo, Christina, Grishaev, Alexander, Bottaro, Sandro, Bergonzo, Christina, Grishaev, Alexander, and Bottaro, Sandro
- Abstract
We describe the conformational ensemble of the single-stranded r(UCAAUC) oligonucleotide obtained using extensive molecular dynamics (MD) simulations and Rosetta's FARFAR2 algorithm. The conformations observed in MD consist of A-form-like structures and variations thereof. These structures are not present in the pool generated using FARFAR2. By comparing with available nuclear magnetic resonance (NMR) measurements, we show that the presence of both A-form-like and other extended conformations is necessary to quantitatively explain experimental data. To further validate our results, we measure solution X-ray scattering (SAXS) data on the RNA hexamer and find that simulations result in more compact structures than observed from these experiments. The integration of simulations with NMR via a maximum entropy approach shows that small modifications to the MD ensemble lead to an improved description of the conformational ensemble. Nevertheless, we identify persisting discrepancies in matching experimental SAXS data.
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- 2022
30. Conformational heterogeneity of UCAAUC RNA oligonucleotide from molecular dynamics simulations, SAXS, and NMR experiments
- Author
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Bergonzo, Christina, primary, Grishaev, Alexander, additional, and Bottaro, Sandro, additional
- Published
- 2022
- Full Text
- View/download PDF
31. MEDTEC Students against Coronavirus: Investigating the Role of Hemostatic Genes in the Predisposition to COVID-19 Severity
- Author
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Cappadona, Claudio, primary, Paraboschi, Elvezia Maria, additional, Ziliotto, Nicole, additional, Bottaro, Sandro, additional, Rimoldi, Valeria, additional, Gerussi, Alessio, additional, Azimonti, Andrea, additional, Brenna, Daniele, additional, Brunati, Andrea, additional, Cameroni, Charlotte, additional, Campanaro, Giovanni, additional, Carloni, Francesca, additional, Cavadini, Giacomo, additional, Ciravegna, Martina, additional, Composto, Antonio, additional, Converso, Giuseppe, additional, Corbella, Pierluigi, additional, D’Eugenio, Davide, additional, Dal Rì, Giovanna, additional, Di Giorgio, Sofia Maria, additional, Grondelli, Maria Chiara, additional, Guerrera, Lorenza, additional, Laffoucriere, Georges, additional, Lando, Beatrice, additional, Lopedote, Leandro, additional, Maizza, Benedetta, additional, Marconi, Elettra, additional, Mariola, Carlotta, additional, Matronola, Guia Margherita, additional, Menga, Luca Maria, additional, Montorsi, Giulia, additional, Papatolo, Antonio, additional, Patti, Riccardo, additional, Profeta, Lorenzo, additional, Rebasti, Vera, additional, Smidili, Alice, additional, Tarchi, Sofia Maria, additional, Tartaglia, Francesco Carlo, additional, Tettamanzi, Gaia, additional, Tinelli, Elena, additional, Stuani, Riccardo, additional, Bolchini, Cristiana, additional, Pattini, Linda, additional, Invernizzi, Pietro, additional, Degenhardt, Frauke, additional, Franke, Andre, additional, Duga, Stefano, additional, and Asselta, Rosanna, additional
- Published
- 2021
- Full Text
- View/download PDF
32. LLM-PBC: Logic Learning Machine-Based Explainable Rules Accurately Stratify the Genetic Risk of Primary Biliary Cholangitis.
- Author
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Gerussi, Alessio, Verda, Damiano, Cappadona, Claudio, Cristoferi, Laura, Bernasconi, Davide Paolo, Bottaro, Sandro, Carbone, Marco, Muselli, Marco, Invernizzi, Pietro, and Asselta, Rosanna
- Subjects
CHOLANGITIS ,LOGIC ,HEBBIAN memory ,FEATURE selection ,LOGICAL prediction ,GENETIC variation - Abstract
Background: The application of Machine Learning (ML) to genetic individual-level data represents a foreseeable advancement for the field, which is still in its infancy. Here, we aimed to evaluate the feasibility and accuracy of an ML-based model for disease risk prediction applied to Primary Biliary Cholangitis (PBC). Methods: Genome-wide significant variants identified in subjects of European ancestry in the recently released second international meta-analysis of GWAS in PBC were used as input data. Quality-checked, individual genomic data from two Italian cohorts were used. The ML included the following steps: import of genotype and phenotype data, genetic variant selection, supervised classification of PBC by genotype, generation of "if-then" rules for disease prediction by logic learning machine (LLM), and model validation in a different cohort. Results: The training cohort included 1345 individuals: 444 were PBC cases and 901 were healthy controls. After pre-processing, 41,899 variants entered the analysis. Several configurations of parameters related to feature selection were simulated. The best LLM model reached an Accuracy of 71.7%, a Matthews correlation coefficient of 0.29, a Youden's value of 0.21, a Sensitivity of 0.28, a Specificity of 0.93, a Positive Predictive Value of 0.66, and a Negative Predictive Value of 0.72. Thirty-eight rules were generated. The rule with the highest covering (19.14) included the following genes: RIN3, KANSL1, TIMMDC1, TNPO3. The validation cohort included 834 individuals: 255 cases and 579 controls. By applying the ruleset derived in the training cohort, the Area under the Curve of the model was 0.73. Conclusions: This study represents the first illustration of an ML model applied to common variants associated with PBC. Our approach is computationally feasible, leverages individual-level data to generate intelligible rules, and can be used for disease prediction in at-risk individuals. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
33. Conformational Ensembles of Noncoding Elements in the SARS-CoV-2 Genome from Molecular Dynamics Simulations
- Author
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Bottaro, Sandro, primary, Bussi, Giovanni, additional, and Lindorff-Larsen, Kresten, additional
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- 2021
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- View/download PDF
34. Conformational Ensembles of Noncoding Elements in the SARS-CoV-2 Genome from Molecular Dynamics Simulations
- Author
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Bottaro, Sandro, Bussi, Giovanni, Lindorff-Larsen, Kresten, Bottaro, Sandro, Bussi, Giovanni, and Lindorff-Larsen, Kresten
- Abstract
The 5′ untranslated region (UTR) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genome is a conserved, functional and structured genomic region consisting of several RNA stem-loop elements. While the secondary structure of such elements has been determined experimentally, their three-dimensional structures are not known yet. Here, we predict structure and dynamics of five RNA stem loops in the 5′-UTR of SARS-CoV-2 by extensive atomistic molecular dynamics simulations, more than 0.5 ms of aggregate simulation time, in combination with enhanced sampling techniques. We compare simulations with available experimental data, describe the resulting conformational ensembles, and identify the presence of specific structural rearrangements in apical and internal loops that may be functionally relevant. Our atomic-detailed structural predictions reveal a rich dynamics in these RNA molecules, could help the experimental characterization of these systems, and provide putative three-dimensional models for structure-based drug design studies.
- Published
- 2021
35. Chapter Three - How to learn from inconsistencies: Integrating molecular simulations with experimental data
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Orioli, Simone, Larsen, Andreas Haahr, Bottaro, Sandro, and Lindorff-Larsen, Kresten
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- 2020
- Full Text
- View/download PDF
36. Conformational Ensembles of Non-Coding Elements in the SARS-CoV-2 Genome from Molecular Dynamics Simulations
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Bottaro, Sandro, primary, Bussi, Giovanni, additional, and Lindorff-Larsen, Kresten, additional
- Published
- 2020
- Full Text
- View/download PDF
37. Structure and dynamics of a nanodisc by integrating NMR, SAXS and SANS experiments with molecular dynamics simulations
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Bengtsen, Tone, primary, Holm, Viktor L, additional, Kjølbye, Lisbeth Ravnkilde, additional, Midtgaard, Søren R, additional, Johansen, Nicolai Tidemand, additional, Tesei, Giulio, additional, Bottaro, Sandro, additional, Schiøtt, Birgit, additional, Arleth, Lise, additional, and Lindorff-Larsen, Kresten, additional
- Published
- 2020
- Full Text
- View/download PDF
38. Author response: Structure and dynamics of a nanodisc by integrating NMR, SAXS and SANS experiments with molecular dynamics simulations
- Author
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Bengtsen, Tone, primary, Holm, Viktor L, additional, Kjølbye, Lisbeth Ravnkilde, additional, Midtgaard, Søren R, additional, Johansen, Nicolai Tidemand, additional, Tesei, Giulio, additional, Bottaro, Sandro, additional, Schiøtt, Birgit, additional, Arleth, Lise, additional, and Lindorff-Larsen, Kresten, additional
- Published
- 2020
- Full Text
- View/download PDF
39. UUCG Tetraloop: And Yet it Moves
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Bottaro, Sandro, primary
- Published
- 2020
- Full Text
- View/download PDF
40. Integrating NMR and simulations reveals motions in the UUCG tetraloop
- Author
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Bottaro, Sandro, primary, Nichols, Parker J, primary, Vögeli, Beat, primary, Parrinello, Michele, primary, and Lindorff-Larsen, Kresten, primary
- Published
- 2020
- Full Text
- View/download PDF
41. Combining molecular dynamics simulations with small-angle X-ray and neutron scattering data to study multi-domain proteins in solution
- Author
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Larsen, Andreas Haahr, primary, Wang, Yong, additional, Bottaro, Sandro, additional, Grudinin, Sergei, additional, Arleth, Lise, additional, and Lindorff-Larsen, Kresten, additional
- Published
- 2020
- Full Text
- View/download PDF
42. Combining molecular dynamics simulations with small-angle X-ray and neutron scattering data to study multi-domain proteins in solution
- Author
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Larsen, Andreas Haahr, Wang, Yong, Bottaro, Sandro, Grudinin, Sergei, Arleth, Lise, Lindorff-Larsen, Kresten, Niels Bohr Institute [Copenhagen] (NBI), Faculty of Science [Copenhagen], University of Copenhagen = Københavns Universitet (UCPH)-University of Copenhagen = Københavns Universitet (UCPH), Structural Bioinformatics and Computational Biochemistry [Oxford] (SBCB), University of Oxford, Linderstrøm-Lang Centre for Protein Science [Copenhagen], IT University of Copenhagen (ITU), Università degli studi di Genova = University of Genoa (UniGe), Algorithms for Modeling and Simulating Nanosystems [2018-...] (NANO-D-POST [2018-2020]), Inria Grenoble - Rhône-Alpes, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), University of Oxford [Oxford], IT University of Copenhagen, Universita degli studi di Genova, Algorithms for Modeling and Simulation of Nanosystems (NANO-D), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Kuntzmann (LJK), Institut National de Recherche en Informatique et en Automatique (Inria)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), Université Grenoble Alpes (UGA)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA)-Institut polytechnique de Grenoble - Grenoble Institute of Technology (Grenoble INP ), and Université Grenoble Alpes (UGA)
- Subjects
0301 basic medicine ,Protein Conformation ,Entropy ,Neutron scattering ,Biochemistry ,01 natural sciences ,Small-Angle Scattering ,Scattering ,Molecular dynamics ,0302 clinical medicine ,X-Ray Diffraction ,Biochemical Simulations ,Macromolecular Structure Analysis ,Statistical physics ,Biology (General) ,Physics ,Quantitative Biology::Biomolecules ,0303 health sciences ,Ecology ,010304 chemical physics ,Small-angle X-ray scattering ,Simulation and Modeling ,Principle of maximum entropy ,[SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics ,Computational Theory and Mathematics ,Modeling and Simulation ,Physical Sciences ,Engineering and Technology ,Thermodynamics ,Small-angle scattering ,Algorithms ,Research Article ,Protein Structure ,Biophysical Simulations ,QH301-705.5 ,Biophysics ,Molecular Dynamics Simulation ,Research and Analysis Methods ,Cellular and Molecular Neuroscience ,03 medical and health sciences ,Protein Domains ,Robustness (computer science) ,Scattering, Small Angle ,0103 physical sciences ,Genetics ,Neutron ,Protein Interactions ,Signal to Noise Ratio ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,030304 developmental biology ,Neutrons ,Biology and Life Sciences ,Computational Biology ,Proteins ,Function (mathematics) ,030104 developmental biology ,Structural biology ,Signal Processing ,030217 neurology & neurosurgery - Abstract
Many proteins contain multiple folded domains separated by flexible linkers, and the ability to describe the structure and conformational heterogeneity of such flexible systems pushes the limits of structural biology. Using the three-domain protein TIA-1 as an example, we here combine coarse-grained molecular dynamics simulations with previously measured small-angle scattering data to study the conformation of TIA-1 in solution. We show that while the coarse-grained potential (Martini) in itself leads to too compact conformations, increasing the strength of protein-water interactions results in ensembles that are in very good agreement with experiments. We show how these ensembles can be refined further using a Bayesian/Maximum Entropy approach, and examine the robustness to errors in the energy function. In particular we find that as long as the initial simulation is relatively good, reweighting against experiments is very robust. We also study the relative information in X-ray and neutron scattering experiments and find that refining against the SAXS experiments leads to improvement in the SANS data. Our results suggest a general strategy for studying the conformation of multi-domain proteins in solution that combines coarse-grained simulations with small-angle X-ray scattering data that are generally most easy to obtain. These results may in turn be used to design further small-angle neutron scattering experiments that exploit contrast variation through 1H/2H isotope substitutions., Author summary Many proteins contain multiple folded domains separated by flexible linkers, and in order to understand how such multi-domain proteins function, we need to be able to describe how these domains are oriented in space. We have used the three-domain protein TIA-1 as an example to combine molecular simulations with biophysical experiments to describe the structural and dynamical properties of a multi-domain protein. We show that while standard simulations do not lead to good agreement with the experimental data, we can improve the agreement substantially by tuning a single parameter in the model that describes the interaction between protein and water. We can gain further information about the system by a more direct integration of the data, and we find that we can provide a detailed and robust description of the relative location of the different domains in TIA-1. The method is general and will be useful to study the relationship between structure, dynamics and function in multi-domain proteins in other systems.
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- 2019
- Full Text
- View/download PDF
43. Structure and dynamics of a nanodisc by integrating NMR, SAXS and SANS experiments with molecular dynamics simulations.
- Author
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Bengtsen, Tone, Midtgaard, Søren Roi, Holm, Viktor Lindahl, Kjølbye, Lisbeth Ravnkilde, Johansen, Nicolai Tidemand, Tesei, Giulio, Bottaro, Sandro, Schiøtt, Birgit, Arleth, Lise, Lindorff-Larsen, Kresten, Bengtsen, Tone, Midtgaard, Søren Roi, Holm, Viktor Lindahl, Kjølbye, Lisbeth Ravnkilde, Johansen, Nicolai Tidemand, Tesei, Giulio, Bottaro, Sandro, Schiøtt, Birgit, Arleth, Lise, and Lindorff-Larsen, Kresten
- Published
- 2020
44. Integrating NMR and simulations reveals motions in the UUCG tetraloop
- Author
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Bottaro, Sandro, Nichols, Parker J., Vögeli, Beat, Parrinello, Michele, Lindorff-Larsen, Kresten, Bottaro, Sandro, Nichols, Parker J., Vögeli, Beat, Parrinello, Michele, and Lindorff-Larsen, Kresten
- Abstract
We provide an atomic-level description of the structure and dynamics of the UUCG RNA stem-loop by combining molecular dynamics simulations with experimental data. The integration of simulations with exact nuclear Overhauser enhancements data allowed us to characterize two distinct states of this molecule. The most stable conformation corresponds to the consensus three-dimensional structure. The second state is characterized by the absence of the peculiar non-Watson-Crick interactions in the loop region. By using machine learning techniques we identify a set of experimental measurements that are most sensitive to the presence of non-native states. We find that although our MD ensemble, as well as the consensus UUCG tetraloop structures, are in good agreement with experiments, there are remaining discrepancies. Together, our results show that (i) the MD simulation overstabilize a non-native loop conformation, (ii) eNOE data support its presence with a population of ≈10% and (iii) the structural interpretation of experimental data for dynamic RNAs is highly complex, even for a simple model system such as the UUCG tetraloop.
- Published
- 2020
45. Combining molecular dynamics simulations with small-angle X-ray and neutron scattering data to study multi-domain proteins in solution
- Author
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Larsen, Andreas Haahr, Wang, Yong, Bottaro, Sandro, Grudinin, Sergei, Arleth, Lise, Lindorff-Larsen, Kresten, Larsen, Andreas Haahr, Wang, Yong, Bottaro, Sandro, Grudinin, Sergei, Arleth, Lise, and Lindorff-Larsen, Kresten
- Published
- 2020
46. Integrating Molecular Simulation and Experimental Data:A Bayesian/Maximum Entropy Reweighting Approach
- Author
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Gáspári, Zoltán, Bottaro, Sandro, Bengtsen, Tone, Lindorff-Larsen, Kresten, Gáspári, Zoltán, Bottaro, Sandro, Bengtsen, Tone, and Lindorff-Larsen, Kresten
- Abstract
We describe a Bayesian/Maximum entropy (BME) procedure and software to construct a conformational ensemble of a biomolecular system by integrating molecular simulations and experimental data. First, an initial conformational ensemble is constructed using, for example, Molecular Dynamics or Monte Carlo simulations. Due to potential inaccuracies in the model and finite sampling effects, properties predicted from simulations may not agree with experimental data. In BME we use the experimental data to refine the simulation so that the new conformational ensemble has the following properties: (1) the calculated averages are close to the experimental values taking uncertainty into account and (2) it maximizes the relative Shannon entropy with respect to the original simulation ensemble. The output of this procedure is a set of optimized weights that can be used to calculate other properties and distributions of these. Here, we provide a practical guide on how to obtain and use such weights, how to choose adjustable parameters and discuss shortcomings of the method.
- Published
- 2020
47. How to learn from inconsistencies:Integrating molecular simulations with experimental data
- Author
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Strodel, Birgit, Barz, Bogdan, Orioli, Simone, Larsen, Andreas Haahr, Bottaro, Sandro, Lindorff-Larsen, Kresten, Strodel, Birgit, Barz, Bogdan, Orioli, Simone, Larsen, Andreas Haahr, Bottaro, Sandro, and Lindorff-Larsen, Kresten
- Abstract
Molecular simulations and biophysical experiments can be used to provide independent and complementary insights into the molecular origin of biological processes. A particularly useful strategy is to use molecular simulations as a modeling tool to interpret experimental measurements, and to use experimental data to refine our biophysical models. Thus, explicit integration and synergy between molecular simulations and experiments is fundamental for furthering our understanding of biological processes. This is especially true in the case where discrepancies between measured and simulated observables emerge. In this chapter, we provide an overview of some of the core ideas behind methods that were developed to improve the consistency between experimental information and numerical predictions. We distinguish between situations where experiments are used to refine our understanding and models of specific systems, and situations where experiments are used more generally to refine transferable models. We discuss different philosophies and attempt to unify them in a single framework. Until now, such integration between experiments and simulations have mostly been applied to equilibrium data, and we discuss more recent developments aimed to analyze time-dependent or time-resolved data.
- Published
- 2020
48. Combining molecular dynamics simulations with small-angle X-ray and neutron scattering data to study multi-domain proteins in solution
- Author
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Larsen, Andreas Haahr, primary, Wang, Yong, additional, Bottaro, Sandro, additional, Grudinin, Sergei, additional, Arleth, Lise, additional, and Lindorff-Larsen, Kresten, additional
- Published
- 2019
- Full Text
- View/download PDF
49. Structure and dynamics of a nanodisc by integrating NMR, SAXS and SANS experiments with molecular dynamics simulations
- Author
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Bengtsen, Tone, primary, Holm, Viktor L., additional, Kjølbye, Lisbeth Ravnkilde, additional, Midtgaard, Søren R., additional, Johansen, Nicolai Tidemand, additional, Tesei, Giulio, additional, Bottaro, Sandro, additional, Schiøtt, Birgit, additional, Arleth, Lise, additional, and Lindorff-Larsen, Kresten, additional
- Published
- 2019
- Full Text
- View/download PDF
50. Integrating NMR and Simulations Reveals Motions in the UUCG Tetraloop
- Author
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Bottaro, Sandro, primary, Nichols, Parker J., additional, Vögeli, Beat, additional, Parrinello, Michele, additional, and Lindorff-Larsen, Kresten, additional
- Published
- 2019
- Full Text
- View/download PDF
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