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4. Performance of the AMOEBA Water Model in the Vicinity of QM Solutes: A Diagnosis Using Energy Decomposition Analysis

Author

Mao, Yuezhi, Shao, Yihan, Dziedzic, Jacek, Skylaris, Chris-Kriton, Head-Gordon, Teresa, and Head-Gordon, Martin

Subjects
Chemical Sciences, Physical Chemistry, Theoretical and Computational Chemistry, Bioengineering, Rare Diseases, Biochemistry and Cell Biology, Computer Software, Chemical Physics, Physical chemistry, Theoretical and computational chemistry
Abstract

The importance of incorporating solvent polarization effects into the modeling of solvation processes has been well-recognized, and therefore a new generation of hybrid quantum mechanics/molecular mechanics (QM/MM) approaches that accounts for this effect is desirable. We present a fully self-consistent, mutually polarizable QM/MM scheme using the AMOEBA force field, in which the total energy of the system is variationally minimized with respect to both the QM electronic density and the MM induced dipoles. This QM/AMOEBA model is implemented through the Q-Chem/LibEFP code interface and then applied to the evaluation of solute-solvent interaction energies for various systems ranging from the water dimer to neutral and ionic solutes (NH3, NH4+, CN-) surrounded by increasing numbers of water molecules (up to 100). In order to analyze the resulting interaction energies, we also utilize an energy decomposition analysis (EDA) scheme which identifies contributions from permanent electrostatics, polarization, and van der Waals (vdW) interaction for the interaction between the QM solute and the solvent molecules described by AMOEBA. This facilitates a component-wise comparison against full QM calculations where the corresponding energy components are obtained via a modified version of the absolutely localized molecular orbitals (ALMO)-EDA. The results show that the present QM/AMOEBA model can yield reasonable solute-solvent interaction energies for neutral and cationic species, while further scrutiny reveals that this accuracy highly relies on the delicate balance between insufficiently favorable permanent electrostatics and softened vdW interaction. For anionic solutes where the charge penetration effect becomes more pronounced, the QM/MM interface turns out to be unbalanced. These results are consistent with and further elucidate our findings in a previous study using a slightly different QM/AMOEBA model ( Dziedzic et al. J. Chem. Phys. 2016 , 145 , 124106 ). The implications of these results for further refinement of this model are also discussed.

Published
2017

5. Performance of extended Lagrangian schemes for molecular dynamics simulations with classical polarizable force fields and density functional theory

Author

Vitale, Valerio, Dziedzic, Jacek, Albaugh, Alex, Niklasson, Anders MN, Head-Gordon, Teresa, and Skylaris, Chris-Kriton

Subjects
Chemical Sciences, Theoretical and Computational Chemistry, Physical Sciences, Engineering, Chemical Physics, Chemical sciences, Physical sciences
Abstract

Iterative energy minimization with the aim of achieving self-consistency is a common feature of Born-Oppenheimer molecular dynamics (BOMD) and classical molecular dynamics with polarizable force fields. In the former, the electronic degrees of freedom are optimized, while the latter often involves an iterative determination of induced point dipoles. The computational effort of the self-consistency procedure can be reduced by re-using converged solutions from previous time steps. However, this must be done carefully, as not to break time-reversal symmetry, which negatively impacts energy conservation. Self-consistent schemes based on the extended Lagrangian formalism, where the initial guesses for the optimized quantities are treated as auxiliary degrees of freedom, constitute one elegant solution. We report on the performance of two integration schemes with the same underlying extended Lagrangian structure, which we both employ in two radically distinct regimes-in classical molecular dynamics simulations with the AMOEBA polarizable force field and in BOMD simulations with the Onetep linear-scaling density functional theory (LS-DFT) approach. Both integration schemes are found to offer significant improvements over the standard (unpropagated) molecular dynamics formulation in both the classical and LS-DFT regimes.

Published
2017

6. Use of the rVV10 Nonlocal Correlation Functional in the B97M‑V Density Functional: Defining B97M-rV and Related Functionals

Author

Mardirossian, Narbe, Pestana, Luis Ruiz, Womack, James C, Skylaris, Chris-Kriton, Head-Gordon, Teresa, and Head-Gordon, Martin

Subjects
Chemical Sciences, Physical Chemistry, Physical Sciences, Chemical sciences, Physical sciences
Abstract

The VV10 and rVV10 nonlocal correlation functionals are consistently implemented and assessed, with the goal of determining if the rVV10 nonlocal correlation functional can replace the VV10 nonlocal correlation functional in the recently developed B97M-V density functional, to give the B97M-rV density functional. Along the way, four density functionals are simultaneously tested: VV10, rVV10, B97M-V, and B97M-rV. An initial assessment is carried out across the S22 data set, and the short-range damping variable, b, is varied for all four density functionals in order to determine the sensitivity of the functionals to the empirical parameter. The results of this test indicate that a value of b = 6 (fortuitously the same as that in B97M-V) is suitable for B97M-rV. The functionals are then compared across an extensive database of interaction energies, and it is demonstrated that B97M-rV either matches or outperforms B97M-V for all of the tests considered. Finally, the optimization of b across the S22 data set is extended to two range-separated hybrid density functionals, ωB97X-V and ωB97M-V, and a value of b = 6.2 is recommended for both ωB97X-rV and ωB97M-rV.

Published
2017

7. Self-consistent implementation of meta-GGA functionals for the ONETEP linear-scaling electronic structure package

Author

Womack, James C, Mardirossian, Narbe, Head-Gordon, Martin, and Skylaris, Chris-Kriton

Subjects
Chemical Sciences, Theoretical and Computational Chemistry, Physical Sciences, Engineering, Chemical Physics, Chemical sciences, Physical sciences
Abstract

Accurate and computationally efficient exchange-correlation functionals are critical to the successful application of linear-scaling density functional theory (DFT). Local and semi-local functionals of the density are naturally compatible with linear-scaling approaches, having a general form which assumes the locality of electronic interactions and which can be efficiently evaluated by numerical quadrature. Presently, the most sophisticated and flexible semi-local functionals are members of the meta-generalized-gradient approximation (meta-GGA) family, and depend upon the kinetic energy density, τ, in addition to the charge density and its gradient. In order to extend the theoretical and computational advantages of τ-dependent meta-GGA functionals to large-scale DFT calculations on thousands of atoms, we have implemented support for τ-dependent meta-GGA functionals in the ONETEP program. In this paper we lay out the theoretical innovations necessary to implement τ-dependent meta-GGA functionals within ONETEP's linear-scaling formalism. We present expressions for the gradient of the τ-dependent exchange-correlation energy, necessary for direct energy minimization. We also derive the forms of the τ-dependent exchange-correlation potential and kinetic energy density in terms of the strictly localized, self-consistently optimized orbitals used by ONETEP. To validate the numerical accuracy of our self-consistent meta-GGA implementation, we performed calculations using the B97M-V and PKZB meta-GGAs on a variety of small molecules. Using only a minimal basis set of self-consistently optimized local orbitals, we obtain energies in excellent agreement with large basis set calculations performed using other codes. Finally, to establish the linear-scaling computational cost and applicability of our approach to large-scale calculations, we present the outcome of self-consistent meta-GGA calculations on amyloid fibrils of increasing size, up to tens of thousands of atoms.

Published
2016

9. An Electronic Structure Investigation of PEDOT with AlCl 4 − Anions—A Promising Redox Combination for Energy Storage Applications.

Author

Craig, Ben, Townsend, Peter, de Leon, Carlos Ponce, Skylaris, Chris-Kriton, and Kramer, Denis

Subjects
ENERGY storage, ANAPLASTIC large-cell lymphoma, ANIONS, OLIGOMERS, POLYMERS, CONDUCTING polymers, ELECTRON distribution, ELECTRONIC structure, POLARONS
Abstract

In this work, we use density functional theory to investigate the electronic structure of poly(3,4-ethylenedioxythiophene) (PEDOT) oligomers with co-located AlCl4− anions, a promising combination for energy storage. The 1980s bipolaron model remains the dominant interpretation of the electronic structure of PEDOT despite recent theoretical progress that has provided new definitions of bipolarons and polarons. By considering the influence of oligomer length, oxidation or anion concentration and spin state, we find no evidence for many of the assertions of the 1980s bipolaron model and so further contribute to a new understanding. No self-localisation of positive charges in PEDOT is found, as predicted by the bipolaron model at the hybrid functional level. Instead, our results show distortions that exhibit a single or a double peak in bond length alternations and charge density. Either can occur at different oxidation or anion concentrations. Rather than representing bipolarons or polaron pairs in the original model, these are electron distributions driven by a range of factors. Distortions can span an arbitrary number of nearby anions. We also contribute a novel conductivity hypothesis. Conductivity in conducting polymers has been observed to reduce at anion concentrations above 0.5. We show that at high anion concentrations, the energy of the localised, non-bonding anionic orbitals approaches that of the system HOMO due to Coulombic repulsion between anions. We hypothesize that with nucleic motion in the macropolymer, these orbitals will interfere with the hopping of charge carriers between sites of similar energy, lowering conductivity. [ABSTRACT FROM AUTHOR]

Published
2024
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10. TINKTEP: A fully self-consistent, mutually polarizable QM/MM approach based on the AMOEBA force field

Author

Dziedzic, Jacek, Mao, Yuezhi, Shao, Yihan, Ponder, Jay, Head-Gordon, Teresa, Head-Gordon, Martin, and Skylaris, Chris-Kriton

Subjects
Physical Sciences, Chemical Sciences, Engineering, Chemical Physics
Abstract

We present a novel quantum mechanical/molecular mechanics (QM/MM) approach in which a quantum subsystem is coupled to a classical subsystem described by the AMOEBA polarizable force field. Our approach permits mutual polarization between the QM and MM subsystems, effected through multipolar electrostatics. Self-consistency is achieved for both the QM and MM subsystems through a total energy minimization scheme. We provide an expression for the Hamiltonian of the coupled QM/MM system, which we minimize using gradient methods. The QM subsystem is described by the onetep linear-scaling DFT approach, which makes use of strictly localized orbitals expressed in a set of periodic sinc basis functions equivalent to plane waves. The MM subsystem is described by the multipolar, polarizable force field AMOEBA, as implemented in tinker. Distributed multipole analysis is used to obtain, on the fly, a classical representation of the QM subsystem in terms of atom-centered multipoles. This auxiliary representation is used for all polarization interactions between QM and MM, allowing us to treat them on the same footing as in AMOEBA. We validate our method in tests of solute-solvent interaction energies, for neutral and charged molecules, demonstrating the simultaneous optimization of the quantum and classical degrees of freedom. Encouragingly, we find that the inclusion of explicit polarization in the MM part of QM/MM improves the agreement with fully QM calculations.

Published
2016

11. Advanced Potential Energy Surfaces for Molecular Simulation

Author

Albaugh, Alex, Boateng, Henry A, Bradshaw, Richard T, Demerdash, Omar N, Dziedzic, Jacek, Mao, Yuezhi, Margul, Daniel T, Swails, Jason, Zeng, Qiao, Case, David A, Eastman, Peter, Wang, Lee-Ping, Essex, Jonathan W, Head-Gordon, Martin, Pande, Vijay S, Ponder, Jay W, Shao, Yihan, Skylaris, Chris-Kriton, Todorov, Ilian T, Tuckerman, Mark E, and Head-Gordon, Teresa

Subjects
Chemical Sciences, Physical Chemistry, Theoretical and Computational Chemistry, Networking and Information Technology R&D (NITRD), Affordable and Clean Energy, Algorithms, Computer Graphics, Molecular Dynamics Simulation, Quantum Theory, Software, Static Electricity, Surface Properties, Physical Sciences, Engineering, Chemical sciences, Physical sciences
Abstract

Advanced potential energy surfaces are defined as theoretical models that explicitly include many-body effects that transcend the standard fixed-charge, pairwise-additive paradigm typically used in molecular simulation. However, several factors relating to their software implementation have precluded their widespread use in condensed-phase simulations: the computational cost of the theoretical models, a paucity of approximate models and algorithmic improvements that can ameliorate their cost, underdeveloped interfaces and limited dissemination in computational code bases that are widely used in the computational chemistry community, and software implementations that have not kept pace with modern high-performance computing (HPC) architectures, such as multicore CPUs and modern graphics processing units (GPUs). In this Feature Article we review recent progress made in these areas, including well-defined polarization approximations and new multipole electrostatic formulations, novel methods for solving the mutual polarization equations and increasing the MD time step, combining linear-scaling electronic structure methods with new QM/MM methods that account for mutual polarization between the two regions, and the greatly improved software deployment of these models and methods onto GPU and CPU hardware platforms. We have now approached an era where multipole-based polarizable force fields can be routinely used to obtain computational results comparable to state-of-the-art density functional theory while reaching sampling statistics that are acceptable when compared to that obtained from simpler fixed partial charge force fields.

Published
2016

12. Approaching the basis set limit for DFT calculations using an environment-adapted minimal basis with perturbation theory: Formulation, proof of concept, and a pilot implementation

Author

Mao, Yuezhi, Horn, Paul R, Mardirossian, Narbe, Head-Gordon, Teresa, Skylaris, Chris-Kriton, and Head-Gordon, Martin

Subjects
Physical Sciences, Chemical Sciences, Engineering, Chemical Physics
Abstract

Recently developed density functionals have good accuracy for both thermochemistry (TC) and non-covalent interactions (NC) if very large atomic orbital basis sets are used. To approach the basis set limit with potentially lower computational cost, a new self-consistent field (SCF) scheme is presented that employs minimal adaptive basis (MAB) functions. The MAB functions are optimized on each atomic site by minimizing a surrogate function. High accuracy is obtained by applying a perturbative correction (PC) to the MAB calculation, similar to dual basis approaches. Compared to exact SCF results, using this MAB-SCF (PC) approach with the same large target basis set produces

Published
2016

13. What Is the Price of Open-Source Software?

Author

Krylov, Anna I, Herbert, John M, Furche, Filipp, Head-Gordon, Martin, Knowles, Peter J, Lindh, Roland, Manby, Frederick R, Pulay, Peter, Skylaris, Chris-Kriton, and Werner, Hans-Joachim

Subjects
Physical Sciences, Chemical Sciences
Published
2015

14. Minimal parameter implicit solvent model for ab initio electronic structure calculations

Author

Dziedzic, Jacek, Helal, Hatem H., Skylaris, Chris-Kriton, Mostofi, Arash A., and Payne, Mike C.

Subjects
Physics - Computational Physics, Physics - Chemical Physics
Abstract

We present an implicit solvent model for ab initio electronic structure calculations which is fully self-consistent and is based on direct solution of the nonhomogeneous Poisson equation. The solute cavity is naturally defined in terms of an isosurface of the electronic density according to the formula of Fattebert and Gygi (J. Comp. Chem. 23, 6 (2002)). While this model depends on only two parameters, we demonstrate that by using appropriate boundary conditions and dispersion-repulsion contributions, solvation energies obtained for an extensive test set including neutral and charged molecules show dramatic improvement compared to existing models. Our approach is implemented in, but not restricted to, a linear-scaling density functional theory (DFT) framework, opening the path for self-consistent implicit solvent DFT calculations on systems of unprecedented size, which we demonstrate with calculations on a 2615-atom protein-ligand complex., Comment: Europhys Lett., 95 (2011)

Published
2011
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15. Novel structural features of CDK inhibition revealed by an ab initio computational method combined with dynamic simulations

Author

Heady, Lucy, Fernandez-Serra, Marivi, Mancera, Ricardo L., Joyce, Sian, Venkitaraman, Ashok R., Artacho, Emilio, Skylaris, Chris-Kriton, Ciacchi, Lucio Colombi, and Payne, Mike C.

Subjects
Physics - Biological Physics, Physics - Computational Physics, Quantitative Biology - Quantitative Methods
Abstract

The rational development of specific inhibitors for the ~500 protein kinases encoded in the human genome is impeded by a poor understanding of the structural basis for the activity and selectivity of small molecules that compete for ATP binding. Combining classical dynamic simulations with a novel ab initio computational approach linear-scalable to molecular interactions involving thousands of atoms, we have investigated the binding of five distinct inhibitors to the cyclin-dependent kinase CDK2. We report here that polarization and dynamic hydrogen bonding effects, so far undetected by crystallography, affect both their activity and selectivity. The effects arise from the specific solvation patterns of water molecules in the ATP binding pocket or the intermittent formation of hydrogen bonds during the dynamics of CDK/inhibitor interactions and explain the unexpectedly high potency of certain inhibitors such as 3-(3H-imidazol-4-ylmethylene)-5-methoxy-1,3-dihydro-indol-2-one (SU9516). The Lys89 residue in the ATP-binding pocket of CDK2 is observed to form temporary hydrogen bonds with the three most potent inhibitors. This residue is replaced in CDK4 by Thr89, whose shorter side-chain cannot form similar bonds, explaining the relative selectivity of the inhibitors for CDK2. Our results provide a generally applicable computational method for the analysis of biomolecular structures and reveal hitherto unrecognized features of the interaction between protein kinases and their inhibitors

Published
2008
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17. Using ONETEP for accurate and efficient O(N) density functional calculations

Author

Skylaris, Chris-Kriton, Haynes, Peter D., Mostofi, Arash A., and Payne, Mike C.

Subjects
Condensed Matter - Materials Science
Abstract

We present a detailed comparison between ONETEP, our linear-scaling density functional method, and the conventional pseudopotential plane wave approach in order to demonstrate its high accuracy. Further comparison with all-electron calculations shows that only the largest available Gaussian basis sets can match the accuracy of routine ONETEP calculations. Results indicate that our minimisation procedure is not ill-conditioned and that convergence to self-consistency is achieved efficiently. Finally we present calculations with ONETEP, on systems of about 1000 atoms, of electronic, structural and chemical properties of a wide variety of materials such as metallic and semiconducting carbon nanotubes, crystalline silicon and a protein complex.

Published
2005
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18. Comparison of variational real-space representations of the kinetic energy operator

Author

Skylaris, Chris-Kriton, Dieguez, Oswaldo, Haynes, Peter D., and Payne, Mike C.

Subjects
Condensed Matter - Materials Science
Abstract

We present a comparison of real-space methods based on regular grids for electronic structure calculations that are designed to have basis set variational properties, using as a reference the conventional method of finite differences (a real-space method that is not variational) and the reciprocal-space plane-wave method which is fully variational. We find that a new definition of the finite differences method [P. Maragakis, J. Soler, and E. Kaxiras, Phys. Rev. B \textbf{64}, 193101 (2001)] satisfies one of the two properties of variational behaviour at the cost of larger errors than the conventional finite differences method. On the other hand, a technique which represents functions in a number of plane-waves which is independent of system size, follows closely the plane-wave method and therefore also the criteria for variational behaviour. Its application is only limited by the requirement of having functions strictly localised in regions of real-space but this is a characteristic of most modern real-space methods as they are designed to have a computational cost that scales linearly with system size., Comment: 9 pages, 3 figures

Published
2001
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19. Accurate kinetic energy evaluation in electronic structure calculations with localised functions on real space grids

Author

Skylaris, Chris-Kriton, Mostofi, Arash A., Haynes, Peter D., Pickard, Chris J., and Payne, Mike C.

Subjects
Condensed Matter - Materials Science
Abstract

We present a method for calculating the kinetic energy of localised functions represented on a regular real space grid. This method uses fast Fourier transforms applied to restricted regions commensurate with the simulation cell and is applicable to grids of any symmetry. In the limit of large systems it scales linearly with system size. Comparison with the finite difference approach shows that our method offers significant improvements in accuracy without loss of efficiency., Comment: Standard Latex article format, 16 pages, 3 figures. Published in Computer Physics Communications vol.140 (2001) pp. 315-322

Published
2001
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24. Cholesteryl esters stabilize human CD1c conformations for recognition by self-reactive T cells

Author

Mansour, Salah, Tocheva, Anna S., Cave-Ayland, Chris, Machelett, Moritz M., Sander, Barbara, Lissin, Nikolai M., Molloy, Peter E., Baird, Mark S., Stübs, Gunthard, Schröder, Nicolas W. J., Schumann, Ralf R., Rademann, Jörg, Postle, Anthony D., Jakobsen, Bent K., Marshall, Ben G., Gosain, Rajendra, Elkington, Paul T., Elliott, Tim, Skylaris, Chris-Kriton, Essex, Jonathan W., Tews, Ivo, and Gadola, Stephan D.

Published
2016

26. Materials and Molecular Modelling at the Exascale

Author

Keal, Thomas, Elena, Alin-Marin, Stoneham, Karen, Probert, Matt, Cucinotta, Clotilde, Zen, Andrea, Hasnip, Philip James, Bush, Ian, Watkins, Matthew, Alfe, Dario, Skylaris, Chris-Kriton, Curchod, Basile, Cai, Qiong, and Woodley, Scott

Abstract

Progression of computational resources towards exascale computing makes possible simulations of unprecedented accuracy and complexity in the fields of materials and molecular modelling (MMM), allowing high fidelity in silico experiments on complex materials of real technological interest. However, this presents demanding challenges for the software used, especially the exploitation of the huge degree of parallelism available on exascale hardware, and the associated problems of developing effective workflows and data management on such platforms. As part of the UKs ExCALIBUR exascale computing initiative, the UK-led MMM Design and Development Working Group has worked with the broad MMM community to identify a set of high priority application case studies which will drive future exascale software developments. We present an overview of these case studies, categorized by the methodological challenges which will be required to realize them on exascale platforms, and discuss the exascale requirements, software challenges and impact of each application area.

Published
2022

30. AI3SD Intern Project: Towards including chemical insights into large-scale quantum chemistry calculations

Author

Vekassy, András, Skylaris, Chris-Kriton, Kanza, Samantha, and Frey, Jeremy G.

Abstract

This year 15 interns join us for a 10 week programme between 28th June and 25th September 2021. The projects they are working on are interdisciplinary and include both cutting-edge AI and cutting-edge chemical discovery and demonstrate how and why they are relevant to AI3SD. The projects must be able to demonstrate valuable outputs both with respect to developing student skill and providing impact to AI3SD.The Interns will be required to produce a poster for the AI3SD Summer Project Symposia 1st – 2nd September 2021, and they will take part in our Skills4Scientists programme that will run weekly across July and August whereby the interns will be given training in a range of research, technical and interpersonal skills, alongside informative career-based events.

Published
2021

31. AI3SD Video: Skills4Scientists - Poster & Careers Symposium - Poster Compilation

Author

Vekassy, András, Fenzl, Aspen, Gulsen, Erhan, Zewdu, Hewan, Longio, Jamie, Hoffman, Maximilian, Barrett, Rhyan, Khondaker, Rubaiyat, Catton, Anna, Dong, Hongyang, Calvache, Kevin, Patel, Kaylee, Wong, King, Greenhalgh, Louis, Clements, Rebecca, Jane, Allam, Thomas, Scripps, Sarah, Man, Gavin, Munday, Samuel, Blakey, Michael, Day, Graeme M., Skylaris, Chris-Kriton, Coles, Simon J., Gow, Stephen, Brocklesby, William, Frey, Jeremy G., Kanza, Samantha, and Knight, Nicola

Abstract

This video forms part of the Skills4Scientists Series which has been organised as a joint venture between the Artificial Intelligence for Scientific Discovery Network+ (AI3SD) and the Physical Sciences Data-Science Service (PSDS). This series ran over summer 2021 and aims to educate and improve scientists skills in a range of areas including research data management, python, version control, ethics, and career development. This series is primarily aimed at final year undergraduates / early stage PhD students. This video is a compilation of posters presented at the Skills4Scientists Posters & Careers Symposium. These poster presentations are predominantly from summer students involved in the AI3SD 2021 summer internship program. Higher resolution versions of the posters are available on the poster symposium website: https://www.ai3sd.org/s4s-symposium20...Not all poster presenters requested a recording of their talk. The following posters recordings are included in this compilation video. Poster 1 - Nearer the nearsightedness principle: Large-scale quantum chemical calculations – Andras Vekassy (University of Southampton) Poster 3 - Combining Ultrasonic Methods and Machine Learning Techniques to Assess Baked Products Quality – Erhan Gulsen (University of Nottingham) Poster 4 - Interactive Knowledge-Based Solvent Selection Tool – Hewan Zewdu (University of Nottingham)Poster 5 - CV in High Throughput Chemistry – Jamie Longino (University of Strathclyde)Poster 9 - Dewetting in Thin Liquid Films: Using Sparse Optimization to Learn Evolution Equations – Aspen Fenzl (University of Sheffield)Poster 12 - Creating a merged dataset and its exploration with different Machine Learning algorithms – Maximilian Hoffman (Freie Universität of Berlin)Poster 14 - Bayesian optimisation in Chemistry – Rubaiyat Khondaker (University of Cambridge) Poster 15 - A deep neural network for generation of functional organic materials – Rhyan Barrett (University of Warwick) Thank you to our sponsors Optibrium (https://www.optibrium.com/) and Dotmatics (https://www.dotmatics.com/) who supported this event. These poster presentations were live cartooned by ErrantScience (errantscience.com) which is also available on our YouTube Channel. Sections Intro: (0:00) Andras Vekassy - Nearer the nearsighted principle: Large-scale quantum chemical calculations: (0:17) Erhan Gulsen - Combining Ultrasonic Methods and Machine Learning Techniques to Assess Baked Products Quality: (06:11) Hewan Zewdu - Interactive Knowledge-Based Solvent Selection Tool: (12:09) Jamie Longino - CV in High Throughput Chemistry: (16:52) Aspen Fenzl - Dewetting in Thin Liquid Films: Using Sparse Optimization to Learn Evolution Equations: (21:21) Maximillian Hoffman - Creating a merged dataset and its exploration with different machine learning algorithms: (27:31) Rubaiyat Khondaker - Bayesian optimisation in Chemistry: (34:33) Rhyan Barrett - A deep neural network for generation of functional organic materials: (40:06) Further details from this series can be found at: https://www.ai3sd.org/skills4scientists This video is an output from the AI3SD Network+ (Artificial Intelligence and Augmented Intelligence for Automated Investigations for Scientific Discovery) which is funded by EPSRC under Grant Number EP/S000356/1 and PSDS (Physical Sciences Data science Service) which is funded by EPSRC under Grant Number EP/S020357/1.

Published
2021

33. ParaMol: A package for parametrization of molecular mechanics force fields

Author

Morado, Joao, Mortenson, Paul N., Verdonk, Marcel L., Ward, Richard A., Essex, Jonathan W., and Skylaris, Chris-Kriton

Abstract

The ensemble of structures generated by molecular mechanics (MM) simulations is determined by the functional form of the force field employed and its parameterization. For a given functional form, the quality of the parameterization is crucial and will determine how accurately we can compute observable properties from simulations. While accurate force field parameterizations are available for biomolecules, such as proteins or DNA, the parameterization of new molecules, such as drug candidates, is particularly challenging as these may involve functional groups and interactions for which accurate parameters may not be available. Here, in an effort to address this problem, we present ParaMol, a Python package that has a special focus on the parameterization of bonded and nonbonded terms of druglike molecules by fitting to ab initio data. We demonstrate the software by deriving bonded terms’ parameters of three widely known drug molecules, viz. aspirin, caffeine, and a norfloxacin analogue, for which we show that, within the constraints of the functional form, the methodologies implemented in ParaMol are able to derive near-ideal parameters. Additionally, we illustrate the best practices to follow when employing specific parameterization routes. We also determine the sensitivity of different fitting data sets, such as relaxed dihedral scans and configurational ensembles, to the parameterization procedure, and discuss the features of the various weighting methods available to weight configurations. Owing to ParaMol’s capabilities, we propose that this software can be introduced as a routine step in the protocol normally employed to parameterize druglike molecules for MM simulations.

Published
2021

36. Hydration of UO2(super 2+) and PuO2(super 2+)

Author

Spencer, Steven, Gagliardi, Laura, Handy, Nicholas C., Ioannau, Andrew G., Skylaris, Chris-Kriton, Willetts, Andrew, and Simper, Adrian M.

Subjects
Hydration -- Research, Solvation -- Research, Actinium -- Research, Plutonium -- Research, Chemicals, plastics and rubber industries
Abstract

The hydration of the actinyl cations, uranyl UO2(super 2+) and plutonyl PuO2(super 2+), has been investigated. Kohn-Sham Density Function Theory calculations using the MAGIC quantuam chemistry code have been performed on the separate uranyl and plutonyl species, and on the complexes AcO2(super 2+).nH2O (AC = U, Pu; N = 4, 5, 6). The results showed that the solvent plays a critical role in the hydration process wherein the solvent molecules were found to behave like actual binding equatorial ligands.

Published
1999

37. Surfactant proteins A and D: trimerized innate immunity proteins with an affinity for viral fusion proteins

Author

Watson, Alastair, Phipps, Maximillian, Clark, Howard, Skylaris, Chris-Kriton, and Madsen, Jens

Subjects
viruses
Abstract

Innate recognition of viruses is an essential part of the immune response to viral pathogens. This is integral to the maintenance of healthy lungs, which are free from infection and efficient at gaseous exchange. An important component of innate immunity in identifying viruses is the family of C-type collagen containing lectins, also known as collectins. These secreted, soluble proteins are pattern recognition receptors (PRRs) which recognise pathogen-associated molecular patterns (PAMPs), including viral glycoproteins. These innate immune proteins are composed of trimerized units which oligomerise into higher-order structures and facilitate clearance of viral pathogens through multiple mechanisms. Similarly, many viral surface proteins form trimeric configurations, despite not showing primary protein sequence similarities across virus classes and families they belong to. In this review, we discuss the role of lung collectins surfactant proteins A and D (SP-A and SP-D) in viral recognition. Particularly, we focus on the structural similarity and complementarity of these trimeric collectins with the trimeric viral fusion proteins with which, we hypothesise, they have elegantly co-evolved. Recombinant versions of these innate immune proteins may have therapeutic potential in a range of infectious and inflammatory lung diseases including as anti-viral therapeutics.

Published
2018

38. Theory as a driving force to understand reactions on nanoparticles: general discussion

Author

Soulantika, Aikaterini, Arrigo, Rosa, Badmus, Kassim, Baletto, Francesca, Boeije, Maurits, Brinkert, Katharina, Bugaev, Aram, Bukhtiyarov, Valerii, Carosso, Michele, Catlow, Richard, Chutia, Arunabhiram, Davies, Philip, De Leeuw, Nora, Dononelli, Wilke, Freund, Hans-Joachim, Friend, Cynthia, Gates, Bruce, Genest, Alexander, Hargreaves, Justin, Hutchings, Graham, Johnston, Roy, Lamberti, Carlo, Marbaix, Julien, Miranda, Caetano Rodrigues, Odarchenko, Yaroslav, Richards, Nia, Russell, Andrea, Selvam, Parasuraman, Sermon, Paul, Shah, Parag, Shevlin, Stephen, Shozi, Mzamo, Skylaris, Chris-Kriton, Soulantica, Katerina, Torrente-Murciano, Laura, Trunschke, Annette, Van Santen, Rutger, Verga, Lucas Garcia, Whiston, Keith, Willock, David, Laboratoire de physique et chimie des nano-objets (LPCNO), Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie de Toulouse (ICT-FR 2599), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Chimie du CNRS (INC)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Institut de Chimie du CNRS (INC), Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut National des Sciences Appliquées (INSA)-Université de Toulouse (UT)-Institut de Chimie de Toulouse (ICT), Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche pour le Développement (IRD)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie de Toulouse (ICT-FR 2599), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche pour le Développement (IRD)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut de Recherche sur les Systèmes Atomiques et Moléculaires Complexes (IRSAMC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Department of Life Sciences, Imperial College London, London, United Kingdom, Research Center for Nanoscale Structure of Matter, Southern Federal University [Rostov-on-Don] (SFEDU), UCL, Dept Chem, London WC1H 0AJ, England, Fritz-Haber-Institut der Max-Planck-Gesellschaft (FHI), Max Planck Society, Dipartimento di Chimica IFM and NIS, Università degli studi di Torino (UNITO), Institut de Science des Matériaux de Mulhouse (IS2M), Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS), Chemistry, University of Southampton, Schuit Institute of Catalysis, and Eindhoven University of Technology [Eindhoven] (TU/e)

Subjects
ADSORPTION, Coordination number, Structure (category theory), Shell (structure), Nanoparticle, SUPPORTED COPPER CHLORIDE, 02 engineering and technology, 010402 general chemistry, 01 natural sciences, DFT, symbols.namesake, Reaction temperature, Error bar, Physical and Theoretical Chemistry, Einstein, ComputingMilieux_MISCELLANEOUS, Physics, CATALYST, Extended X-ray absorption fine structure, ZEOLITES, CO OXIDATION, OXIDE, 021001 nanoscience & nanotechnology, 0104 chemical sciences, [CHIM.THEO]Chemical Sciences/Theoretical and/or physical chemistry, Chemical physics, X-RAY-ABSORPTION, symbols, METHANOL, 0210 nano-technology, CU
Abstract

International audience; Carlo Lamberti opened discussion of the introductory lecture by Bruce Gates: As you have shown, EXAFS plays a crucial role in determining the structure and the nuclearity of nanoparticles (NPs). For each shell, the accuracy of this determination depends on the error bar associated to the coordination number, that strongly correlates with the corresponding Debye–Waller (DW) parameter. This becomes even more important when in situ operando experiments are performed at reaction temperature. Based on your experience, what suggestions can you give to reduce this correlation and increase the potentiality of the technique? Do you believe it is possible to fix or to determine, in a reliable way, DW parameters from independent experimental or computational works? Do you believe that in temperature-dependent experiments it is reliable to adopt th eDebye or the Einstein model to parametrize the evolution of DW parameters?

Published
2018

39. DL_MG : A Parallel Multigrid Poisson and Poisson–Boltzmann Solver for Electronic Structure Calculations in Vacuum and Solution

Author

Probert, Matthew Ian James, Womack, James, Anton, Lucian, Dziedzic, Jacek, Hasnip, Philip James, and Skylaris, Chris-Kriton

Abstract

The solution of the Poisson equation is a crucial step in electronic structure calculations, yielding the electrostatic potential—a key component of the quantum mechanical Hamiltonian. In recent decades, theoretical advances and increases in computer performance have made it possible to simulate the electronic structure of extended systems in complex environments. This requires the solution of more complicated variants of the Poisson equation, featuring nonhomogeneous dielectric permittivities, ionic concentrations with nonlinear dependencies, and diverse boundary conditions. The analytic solutions generally used to solve the Poisson equation in vacuum (or with homogeneous permittivity) are not applicable in these circumstances, and numerical methods must be used. In this work, we present DL_MG, a flexible, scalable, and accurate solver library, developed specifically to tackle the challenges of solving the Poisson equation in modern large-scale electronic structure calculations on parallel computers. Our solver is based on the multigrid approach and uses an iterative high-order defect correction method to improve the accuracy of solutions. Using two chemically relevant model systems, we tested the accuracy and computational performance of DL_MG when solving the generalized Poisson and Poisson–Boltzmann equations, demonstrating excellent agreement with analytic solutions and efficient scaling to ∼10^9 unknowns and 100s of CPU cores. We also applied DL_MG in actual large-scale electronic structure calculations, using the ONETEP linear-scaling electronic structure package to study a 2615 atom protein–ligand complex with routinely available computational resources. In these calculations, the overall execution time with DL_MG was not significantly greater than the time required for calculations using a conventional FFT-based solver.

Published
2018

40. Field-effect sensors – from pH sensing to biosensing: sensitivity enhancement using streptavidin-biotin as a model system

Author

Lowe, Benjamin M., Sun, Kai, Zeimpekis, Ioannis, Skylaris, Chris-Kriton, and Green, Nicolas G.

Abstract

Field-Effect Transistor sensors (FET-sensors) have been receiving increasing attention for biomolecular sensing over the last two decades due to their potential for ultra-high sensitivity sensing, label-free operation, cost reduction and miniaturisation. Whilst the commercial application of FET-sensors in pH sensing has been realised, their commercial application in biomolecular sensing (termed BioFETs) is hindered by poor understanding of how to optimise device design for highly reproducible operation and high sensitivity. In part, these problems stem from the highly interdisciplinary nature of the problems encountered in this field, in which knowledge of biomolecular-binding kinetics, surface chemistry, electrical double layer physics and electrical engineering is required. In this work, a quantitative analysis and critical review has been performed comparing literature FET-sensor data for pH-sensing with data for sensing of biomolecular streptavidin binding to surface-bound biotin systems. The aim is to provide the first systematic, quantitative comparison of BioFET results for a single biomolecular analyte, specifically Streptavidin, which is the most commonly used model protein in biosensing experiments, and often used as an initial proof-of-concept for new biosensor designs. This novel quantitative and comparative analysis of the surface potential behaviour of a range of devices demonstrated a strong contrast between the trends observed in pH-sensing and those in biomolecule-sensing. Potential explanations are discussed in detail and surface-chemistry optimisation is shown to be a vital component in sensitivity-enhancement. Factors which can influence the response, yet which have not always been fully appreciated, are explored and practical suggestions are provided on how to improve experimental design.

Published
2017

42. Interrogation of the protein-protein interactions between human BRCA2 BRC repeats and RAD51 reveals atomistic determinants of affinity

Author

Kowalczykowski, Stephen Charles, Cole, Daniel J., Rajendra, Eason, Roberts-Thomson, Meredith, Hardwick, Bryn, McKenzie, Grahame J., Payne, Mike C., Venkitaraman, Ashok R., Skylaris, Chris-Kriton, Payne, Michael [0000-0002-5250-8549], and Apollo - University of Cambridge Repository

Subjects
Models, Molecular, Amino Acid Motifs, Plasma protein binding, Molecular Dynamics, medicine.disease_cause, Biochemistry, Biophysics Simulations, 01 natural sciences, chemistry.chemical_compound, Computational Chemistry, Fluorescence Polarization Immunoassay, Protein Interaction Mapping, Recombinase, Biology (General), Biomacromolecule-Ligand Interactions, Peptide sequence, Density Functional Theory, Genetics, 0303 health sciences, Mutation, Ecology, Protein Stability, Physics, Chemistry, Computational Theory and Mathematics, Modeling and Simulation, Interdisciplinary Physics, Thermodynamics, Research Article, Protein Binding, Repetitive Sequences, Amino Acid, QH301-705.5, Molecular Sequence Data, Biophysics, Chemical biology, Sequence alignment, Biology, 010402 general chemistry, Protein–protein interaction, 03 medical and health sciences, Cellular and Molecular Neuroscience, medicine, Humans, Protein Interaction Domains and Motifs, Amino Acid Sequence, Protein Interactions, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Quantum Mechanics, 030304 developmental biology, BRCA2 Protein, Proteins, 0104 chemical sciences, chemistry, Rad51 Recombinase, Sequence Alignment, DNA
Abstract

The breast cancer suppressor BRCA2 controls the recombinase RAD51 in the reactions that mediate homologous DNA recombination, an essential cellular process required for the error-free repair of DNA double-stranded breaks. The primary mode of interaction between BRCA2 and RAD51 is through the BRC repeats, which are ∼35 residue peptide motifs that interact directly with RAD51 in vitro. Human BRCA2, like its mammalian orthologues, contains 8 BRC repeats whose sequence and spacing are evolutionarily conserved. Despite their sequence conservation, there is evidence that the different human BRC repeats have distinct capacities to bind RAD51. A previously published crystal structure reports the structural basis of the interaction between human BRC4 and the catalytic core domain of RAD51. However, no structural information is available regarding the binding of the remaining seven BRC repeats to RAD51, nor is it known why the BRC repeats show marked variation in binding affinity to RAD51 despite only subtle sequence variation. To address these issues, we have performed fluorescence polarisation assays to indirectly measure relative binding affinity, and applied computational simulations to interrogate the behaviour of the eight human BRC-RAD51 complexes, as well as a suite of BRC cancer-associated mutations. Our computational approaches encompass a range of techniques designed to link sequence variation with binding free energy. They include MM-PBSA and thermodynamic integration, which are based on classical force fields, and a recently developed approach to computing binding free energies from large-scale quantum mechanical first principles calculations with the linear-scaling density functional code onetep. Our findings not only reveal how sequence variation in the BRC repeats directly affects affinity with RAD51 and provide significant new insights into the control of RAD51 by human BRCA2, but also exemplify a palette of computational and experimental tools for the analysis of protein-protein interactions for chemical biology and molecular therapeutics., Author Summary The atomic scale interactions that occur at the interfaces between proteins are fundamental to all biological processes. One such critical interface is formed between the proteins, human BRCA2 and RAD51. BRCA2 binds to and delivers RAD51 to sites of DNA damage, where RAD51 mediates the error-free repair of double-stranded DNA breaks. Mutations in BRCA2 have been linked to breast cancer predisposition. Therefore, an accurate picture of the interactions between these two proteins is of great importance. BRCA2 interacts with RAD51 via eight “BRC repeats” that are similar, but not identical, in sequence. Due to lack of experimental structural information regarding the binding of seven of the eight BRC repeats to RAD51, it is unknown how subtle sequence variations in the repeats translate to measurable variations in their binding affinity. We have used a range of computational methods, firstly based on classical force fields, and secondly based on first principles quantum mechanical techniques whose computational cost scales linearly with the number of atoms, allowing us to perform calculations on the entire protein complex. This is the first study comparing all eight BRC repeats at the atomic scale and our results provide critical insights into the control of RAD51 by human BRCA2.

Published
2017
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43. Effect of polymerization statistics on the electronic properties of copolymers for organic photovoltaics

Author

Boschetto, Gabriele, Xue, Hong-Tao, Dziedzic, Jacek, Krompiec, Michal, and Skylaris, Chris-Kriton

Abstract

Statistical block copolymers, composed of donor (D) and acceptor (A) blocks, are a novel type of material for organic photovoltaics (OPVs) devices. In particular a new series of polymers based on PBTZT-stat-BDTT-8, recently developed by Merck, offers high solubility in different solvents, and a high power conversion efficiency (PCE) in different device architectures. Although it is known that the electronic properties of these materials may be significantly affected by attaching different functional groups on different blocks, it is not fully clear how important the influence of the polymer composition (i.e., the D/A block ratio) is, even if previous studies suggest that this might also have an effect. Therefore, the effect of the polymer composition in terms of HOMO, LUMO energies, and band gap was explored by studying a number of long chain oligomers with more than 1000 atoms each and with different D/A ratios. This study, that is novel both conceptually and methodologically, was made possible by using the linear-scaling reformulation of DFT implemented in the ONETEP code. Our results showed that changing the composition has a significant effect on the electronic structure of statistical copolymers, making this an alternative and suitable strategy to obtain materials with desired properties. Also, a systematic analysis of the effect of a range of different substituents placed in the D and A blocks of PBTZT-stat-BDTT-8 was performed in order to investigate how this class of materials responds to functionalization. We found that it is not possible to know a priori using chemical intuition what kind of influence different types of functional groups may have on these systems, and therefore, computational modeling is essential.

Published
2017

44. Ab initiomolecular dynamics study of AlCl4−adsorption on PEDOT conducting polymer chains

Author

Craig, Ben, Skylaris, Chris-Kriton, de Leon, Carlos Ponce, and Kramer, Denis

Abstract

In the search for alternatives to lithium batteries, aluminium makes a promising negative electrode due to its high theoretical specific energy and energy density. One battery chemistry making use of an aluminium negative electrode is the aluminium–poly(3,4-ethylenedioxythiophene) (PEDOT) battery, which has been shown to have long cycle life and specific energy comparable to other aluminium rechargeable batteries. The battery stores AlCl4−anions in the PEDOT cathode when charged. However, the storage mechanism is not well understood. Here, ab initiomolecular dynamics simulations (AIMD) are used to help understand the optimum (relaxed) configuration of AlCl4−anions when stored on a single chain of PEDOT. Two main conclusions arise. Firstly, it is generally not stable to have two anions adsorbed to one monomer unit, and this configuration can be avoided for future work. Secondly, AIMD does not find lower energy configurations for the PEDOT/AlCl4−system than DFT geometry relaxation, providing that the starting geometry does not have two anions on the same monomer unit. Based on our results, we believe it is likely that similar behaviour will be observed in other conducting polymer systems.

Published
2021
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45. Torsional anharmonicity in the conformational analysis of beta-D-galactose

Author

Sturdy, Yvette K., Skylaris, Chris-Kriton, and Clary, David C.

Subjects
Biomolecules -- Electric properties, Biomolecules -- Mechanical properties, Monte Carlo method -- Usage, Harmonic motion -- Research, Chemicals, plastics and rubber industries
Abstract

Schemes to include a treatment of torsional anharmonicity in the conformational analysis of biological molecules are introduced. The approaches combine ab initio electronic energies and harmonic frequencies with unharmonic torsional partition functions calculated using the torsional path integral Monte Carlo method on affordable potential energy surfaces.

Published
2006

47. Optimised three-dimensional Fourier interpolation: An analysis of techniques and application to a linear-scaling density functional theory code

Author

Russell, Francis P., Wilkinson, Karl A., Kelly, Paul H.J., and Skylaris, Chris-Kriton

Subjects
ONETEP, Hardware and Architecture, Trigonometric interpolation, Fast Fourier Transform, Density functional theory, Physics and Astronomy(all)
Abstract

The Fourier interpolation of 3D data-sets is a performance critical operation in many fields, including certain forms of image processing and density functional theory (DFT) quantum chemistry codes based on plane wave basis sets, to which this paper is targeted. In this paper we describe three different algorithms for performing this operation built from standard discrete Fourier transform operations, and derive theoretical operation counts. The algorithms compared consist of the most straightforward implementation and two that exploit techniques such as phase-shifts and knowledge of zero padding to reduce computational cost. Through a library implementation (tintl) we explore the performance characteristics of these algorithms and the performance impact of different implementation choices on actual hardware. We present comparisons within the linear-scaling DFT code ONETEP where we replace the existing interpolation implementation with our library implementation configured to choose the most efficient algorithm. Within the ONETEP Fourier interpolation stages, we demonstrate speed-ups of over 1.55×.

Published
2015

49. Chemically Selective Alternatives to Photoferroelectrics for Polarization‐Enhanced Photocatalysis: The Untapped Potential of Hybrid Inorganic Nanotubes

Author

Elliott, Joshua D., primary, Poli, Emiliano, additional, Scivetti, Ivan, additional, Ratcliff, Laura E., additional, Andrinopoulos, Lampros, additional, Dziedzic, Jacek, additional, Hine, Nicholas D. M., additional, Mostofi, Arash A., additional, Skylaris, Chris‐Kriton, additional, Haynes, Peter D., additional, and Teobaldi, Gilberto, additional

Published
2016
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50. CD1b-restricted GEM T cell responses are modulated by Mycobacterium tuberculosis mycolic acid meromycolate chains.

Author

Tezera, Liku, Chancellor, Andrew, Tocheva, Anna S., Mansour, Salah, Marshall, Ben, Elkington, Paul, Tebruegge, Marc, Gadola, Stephan, Wilson, Susan, Lissini, Nikolai M., White, Andrew, Sharpe, Sally, Cave-Ayland, Chris, Skylaris, Chris-Kriton, Essex, Jonathan W., Al Dulayymi, Juma'a R., Baird, Mark S., Bridgeman, John S., Tews, Ivo, and Elliott, Tim

Subjects
TUBERCULOSIS, T cells, GRANULOMA, MYCOLIC acids, INFECTIOUS disease transmission
Abstract

Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains a major human pandemic. Germline-encoded mycolyl lipid-reactive (GEM) T cells are donor-unrestricted and recognize CD1b-presented mycobacterial mycolates. However, the molecular requirements governing mycolate antigenicity for the GEM T cell receptor (TCR) remain poorly understood. Here, we demonstrate CD1b expression in TB granulomas and reveal a central role for meromycolate chains in influencing GEM-TCR activity. Meromycolate fine structure influences T cell responses in TB-exposed individuals and meromycolate alterations modulate functional responses by GEM-TCRs. Computational simulations suggest that meromycolate chain dynamics regulate mycolate head group movement, thereby modulating GEM-TCR activity. Our findings have significant implications for the design of future vaccines that target GEM T cells. [ABSTRACT FROM AUTHOR]

Published
2017
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