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Solution-processing of organic light-emitting diode films has potential advantages in terms of cost and scalability over vacuum-deposition for large area applications. However, solution processed small molecule films can have lower overall device performance. Here, novel molecular dynamics techniques are developed to enable faster simulation of solvent evaporation that occurs during solution processing and give films of thicknesses relevant to real devices. All-atom molecular dynamics simulations are then used in combination with kinetic Monte Carlo transport modeling to examine how differences in morphology stemming from solution or vacuum film deposition affect charge transport and exciton dynamics in films consisting of light-emitting bis(2-phenylpyridine)(acetylacetonate)iridium(III) [Ir(ppy)2(acac)] guest molecules in a 4,4′-bis(N-carbazolyl)biphenyl host. While the structures of the films deposited from vacuum and solution were found to differ, critically, only minor variations in the transport properties were predicted by the simulations even if trapped solvent was present. [ABSTRACT FROM AUTHOR]

Emissive layers in phosphorescent organic light-emitting diodes commonly make use of guest–host blends such as Ir(ppy)3:CBP to achieve high external quantum efficiencies. However, while the Ir(ppy)3:CBP blend has been studied experimentally, crucial questions remain regarding how exciton diffusion is dependent on the distribution of the guest in the host, which can currently only be addressed at the atomic level via computational modeling. In this work, kinetic Monte Carlo simulations are utilized to gain insight into exciton diffusion in Ir(ppy)3:CBP blend films. The effects of both guest concentration and exciton density on various system properties are analyzed, including the probability of singlet excitons being converted to triplets, and the probability of those triplets decaying radiatively. Significantly, these simulations suggest that triplet diffusion occurs almost exclusively via guest–guest Dexter transfer and that concentration quenching of triplets induced by guest–guest intermolecular dipole-dipole interactions has a negligible effect at high exciton densities due to the prevalence of triplet–triplet annihilation. Furthermore, results for vacuum deposited morphologies derived from molecular dynamics simulations are compared to the results obtained using a simple cubic lattice approximation with randomly distributed guest molecules. We show that while differences in host-based processes such as singlet diffusion are observed, overall, the results on the fate of the excitons are in good agreement for the two morphology types, particularly for guest-based processes at low guest concentrations where guest clustering is limited. [ABSTRACT FROM AUTHOR]

An Online tool for Fragment-based Molecule Parametrization (OFraMP) is described. OFraMP is a web application for assigning atomic interaction parameters to large molecules by matching sub-fragments within the target molecule to equivalent sub-fragments within the Automated Topology Builder (ATB, atb.uq.edu.au) database. OFraMP identifies and compares alternative molecular fragments from the ATB database, which contains over 890,000 pre-parameterized molecules, using a novel hierarchical matching procedure. Atoms are considered within the context of an extended local environment (buffer region) with the degree of similarity between an atom in the target molecule and that in the proposed match controlled by varying the size of the buffer region. Adjacent matching atoms are combined into progressively larger matched sub-structures. The user then selects the most appropriate match. OFraMP also allows users to manually alter interaction parameters and automates the submission of missing substructures to the ATB in order to generate parameters for atoms in environments not represented in the existing database. The utility of OFraMP is illustrated using the anti-cancer agent paclitaxel and a dendrimer used in organic semiconductor devices. OFraMP applied to paclitaxel (ATB ID 35922). [ABSTRACT FROM AUTHOR]

α‐Helical membrane‐active antimicrobial peptides (AMPs) are known to act via a range of mechanisms, including the formation of barrel‐stave and toroidal pores and the micellisation of the membrane (carpet mechanism). Different mechanisms imply that the peptides adopt different 3D structures when bound at the water–membrane interface, a highly amphipathic environment. Here, an evolutionary algorithm is used to predict the 3D structure of a range of α‐helical membrane‐active AMPs at the water–membrane interface by optimising amphipathicity. This amphipathic structure prediction (ASP) is capable of distinguishing between curved and linear peptides solved experimentally, potentially allowing the activity and mechanism of action of different membrane‐active AMPs to be predicted. The ASP algorithm is accessible via a web interface at http://atb.uq.edu.au/asp/. [ABSTRACT FROM AUTHOR]

Phosphorescent emissive materials in organic light‐emitting diodes (OLEDs) manufactured using evaporation are usually blended with host materials at a concentration of 3–15 wt% to avoid concentration quenching of the luminescence. Here, experimental measurements of hole mobility and photoluminescence are related to the atomic level morphology of films created using atomistic nonequilibrium molecular dynamics simulations mimicking the evaporation process with similar guest concentrations as those used in operational test devices. For blends of fac‐tris[2‐phenylpyridinato‐C2,N]iridium(III) [Ir(ppy)3] in tris(4‐carbazoyl‐9‐ylphenyl)amine (TCTA), it is found that clustering of the Ir(ppy)3 (surface of the molecules within ≈0.4 nm) in the simulated films is directly relatable to the experimentally‐measured hole mobility. Films containing 1–10 wt% of Ir(ppy)3 in TCTA have a mobility of up to two orders of magnitude lower (≈10−6 cm2 V−1 s−1) than the neat TCTA film, which is consistent with the Ir(ppy)3 molecules acting as hole traps due to their smaller ionization potential. Comparison of the simulated film morphologies with the measured photoluminescence properties shows that for luminescence quenching to occur, the Ir(ppy)3 molecules have to have their ligands partially overlapping. Thus, the results show that the effect of guest interactions on charge transport and luminescence are markedly different for OLED light‐emitting layers. [ABSTRACT FROM AUTHOR]

The relative binding free energy between two ligands to a specific protein can be obtained using various computational methods. The more accurate and also computationally more demanding techniques are the so-called free energy methods which use conformational sampling from molecular dynamics or Monte Carlo simulations to generate thermodynamic averages. Two such widely applied methods are the thermodynamic integration (TI) and the recently introduced enveloping distribution sampling (EDS) methods. In both cases relative binding free energies are obtained through the alchemical perturbations of one ligand into another in water and inside the binding pocket of the protein. TI requires many separate simulations and the specification of a pathway along which the system is perturbed from one ligand to another. Using the EDS approach, only a single automatically derived reference state enveloping both end states needs to be sampled. In addition, the choice of an optimal pathway in TI calculations is not trivial and a poor choice may lead to poor convergence along the pathway. Given this, EDS is expected to be a valuable and computationally efficient alternative to TI. In this study, the performances of these two methods are compared using the binding of ten tetrahydroisoquinoline derivatives to phenylethanolamine N-transferase as an example. The ligands involve a diverse set of functional groups leading to a wide range of free energy differences. In addition, two different schemes to determine automatically the EDS reference state parameters and two different topology approaches are compared. [ABSTRACT FROM AUTHOR]

Replica exchange methods (REMs) are increasingly used to improve sampling in molecular dynamics (MD) simulations of biomolecular systems. However, despite having been shown to be very effective on model systems, the application of REM in complex systems such as for the simulation of protein and peptide folding in explicit solvent has not been objectively tested in detail. Here we present a comparison of conventional MD and temperature replica exchange MD (T-REMD) simulations of a β-heptapeptide in explicit solvent. This system has previously been shown to undergo reversible folding on the time scales accessible to MD simulation and thus allows a direct one-to-one comparison of efficiency. The primary properties compared are the free energy of folding and the relative populations of different conformers as a function of temperature. It is found that to achieve a similar degree of precision T-REMD simulations starting from a random set of initial configurations were approximately an order of magnitude more computationally efficient than a single 800 ns conventional MD simulation for this system at the lowest temperature investigated (275 K). However, whereas it was found that T-REMD simulations are more than four times more efficient than multiple independent MD simulations at one temperature (300 K) the actual increase in conformation sampling was only twofold. The overall gain in efficiency using REMD resulted primarily from the ordering of different conformational states over temperature, as opposed to a large increase of conformational sampling. It is also shown that in this system exchanges are accepted primarily based on (random) fluctuations within the solvent and are not strongly correlated with the instantaneous peptide conformation raising questions in regard to the efficiency of T-REMD in larger systems. [ABSTRACT FROM AUTHOR]

Despite extensive study the phase behavior of phospholipid monolayers at an air–water interface is still not fully understood. In particular recent vibrational sum-frequency generation (VSFG) spectra of DPPC monolayers as a function of area density show a sharp transition in the order of the lipid chains at 1.10 nm2/molecule. This is in a region where the lateral pressure as a function of area is effectively constant. We have investigated the nature of this transition by studying the phase behavior of DPPC monolayers as a function of area density using molecular-dynamics simulations. The changes in order within the monolayer as a function of area density correlate well with the experimental signal. At 0.58 nm2/molecule we observe the onset of lateral separation of highly ordered and disordered lipids, indicating the coexistence of a gel-like liquid condensed and a fluidlike liquid expanded phase. At 0.97 nm2/molecule the monolayer ruptures, marking the onset of the liquid–gas (G) coexistence region. This is much earlier than suggested by fluorescence microscopy results and implies that at the point of rupture, the initial pores have an equilibrium size smaller than ∼500 nm in diameter. The rupture of the monolayer leads to a sharp increase in the overall lipid order that explains the sharp transition observed in the VSFG measurements. VSFG measurements thus may represent a sensitive means to determine the onset of the liquid–gas (G) coexistence region for such systems. © 2005 American Institute of Physics. [ABSTRACT FROM AUTHOR]

We report results from molecular dynamics simulations of the freezing transition of TIP5P water molecules confined between two parallel plates under the influence of a homogeneous external electric field, with magnitude of 5 V/nm, along the lateral direction. For water confined to a thickness of a trilayer we find two different phases of ice at a temperature of T=280 K. The transformation between the two, proton-ordered, ice phases is found to be a strong first-order transition. The low-density ice phase is built from hexagonal rings parallel to the confining walls and corresponds to the structure of cubic ice. The high-density ice phase has an in-plane rhombic symmetry of the oxygen atoms and larger distortion of hydrogen bond angles. The short-range order of the two ice phases is the same as the local structure of the two bilayer phases of liquid water found recently in the absence of an electric field [J. Chem. Phys. 119, 1694 (2003)]. These high- and low-density phases of water differ in local ordering at the level of the second shell of nearest neighbors. The results reported in this paper, show a close similarity between the local structure of the liquid phase and the short-range order of the corresponding solid phase. This similarity might be enhanced in water due to the deep attractive well characterizing hydrogen bond interactions. We also investigate the low-density ice phase confined to a thickness of 4, 5, and 8 molecular layers under the influence of an electric field at T=300 K. In general, we find that the degree of ordering decreases as the distance between the two confining walls increases.© 2004 American Institute of Physics. [ABSTRACT FROM AUTHOR]

We report results from molecular dynamics simulations of the freezing and melting, at ambient temperature (T = 300 K), of a bilayer of liquid water induced by either changing the distance between two confining parallel walls at constant lateral pressure or by lateral compression at constant plate separation. Both transitions are found to be first order. The system studied consisted of 1200 water molecules that were described by the TIP5P model. The in-plane symmetry of the oxygen atoms in the ice bilayer was found to be rhombic with a distorted in-registry arrangement. Above and below the stability region of the ice bilayer we observed two bilayer phases of liquid water that differ in the local ordering at the level of the second shell of nearest neighbors and in the density profile normal to the plane, yielding two liquid phases with different densities. These results suggest the intriguing possibility of a liquid-liquid transition of water, confined to a bilayer, at regions where the ice bilayer is unstable with respect to either of the liquid phases. In addition, we find that under the same conditions, water confined to 3-8 layers remains in the liquid phase (albeit stratification of the transverse density profile) with values of the lateral diffusion coefficient comparable to that of the bulk. [ABSTRACT FROM AUTHOR]

Biobutanol production by fermentation is potentially a sustainable alternative to butanol production from fossil fuels. However, the toxicity of butanol to fermentative bacteria, resulting largely from cell membrane fluidization, limits production titers and is a major factor limiting the uptake of the technology. Here, studies were undertaken, in vitro and in silico, on the butanol effects on a representative bacterial (i.e. Escherichia coli) inner cell membrane. A critical butanol : lipid ratio for stability of 2 : 1 was observed, computationally, consistent with complete interdigitation. However, at this ratio the bilayer was ∼20% thicker than for full interdigitation. Furthermore, butanol intercalation induced acyl chain bending and increased disorder, measured as a 27% lateral diffusivity increase experimentally in a supported lipid bilayer. There was also a monophasic Tm reduction in butanol-treated large unilamellar vesicles. Both behaviours are inconsistent with an interdigitated gel. Butanol thus causes only partial interdigitation at physiological temperatures, due to butanol accumulating at the phospholipid headgroups. Acyl tail disordering (i.e. splaying and bending) fills the subsequent voids. Finally, butanol short-circuits the bilayer and creates a coupled system where interdigitated and splayed phospholipids coexist. These findings will inform the design of strategies targeting bilayer stability for increasing biobutanol production titers. [ABSTRACT FROM AUTHOR]

Examines the validation of results obtained by computer simulation of molecular systems. Impact of the accuracy of the interatomic interaction function on the overall quality of the simulated properties of the system; Formulation of guidelines for the improvement of the validation of simulation results; Analysis on issues on the validation of the molecular dynamics simulation.

A general method is presented to reduce the simulation time required to compute the relative free energy between two states X and Y of a molecular system by computer simulation. Although the free energy difference ΔAx→y is, in principle, independent of the pathway chosen to change X into Y, in practice its choice strongly affects the accuracy of the obtained ΔA value. The optimum path is the one for which the relaxation time of the system τsystem attains a minimum, allowing the system to remain as close as possible near equilibrium during a simulation. Downscaling the relevant parts of the potential energy function before the change from X to Y is made, and upscaling afterwards is a rather general way to shorten τsystem and thus save computing time. For a model system of butane like molecules the proposed procedure is more than 1 order of magnitude more efficient than the conventional technique of direct interconversion from state X to state Y. [ABSTRACT FROM AUTHOR]

Despite decades of research, the mechanism of action of the ABC multidrug transporter P-glycoprotein (P-gp) remains elusive. Due to experimental limitations, many researchers have turned to molecular dynamics simulation studies in order to investigate different aspects of P-gp function. However, such studies are challenging and caution is required when interpreting the results. P-gp is highly flexible and the time scale on which it can be simulated is limited. There is also uncertainty regarding the accuracy of the various crystal structures available, let alone the structure of the protein in a physiologically relevant environment. In this study, three alternative structural models of mouse P-gp (3G5U, 4KSB, 4M1M), all resolved to 3.8 Å, were used to initiate sets of simulations of P-gp in a membrane environment in order to determine: a) the sensitivity of the results to differences in the starting configuration; and b) the extent to which converged results could be expected on the times scales commonly simulated for this system. The simulations suggest that the arrangement of the nucleotide binding domains (NBDs) observed in the crystal structures is not stable in a membrane environment. In all simulations, the NBDs rapidly associated (within 10 ns) and changes within the transmembrane helices were observed. The secondary structure within the transmembrane domain was best preserved in the 4M1M model under the simulation conditions used. However, the extent to which replicate simulations diverged on a 100 to 200 ns timescale meant that it was not possible to draw definitive conclusions as to which structure overall was most stable, or to obtain converged and reliable results for any of the properties examined. The work brings into question the reliability of conclusions made in regard to the nature of specific interactions inferred from previous simulation studies on this system involving similar sampling times. It also highlights the need to demonstrate the statistical significance of any results obtained in simulations of large flexible proteins, especially where the initial structure is uncertain. [ABSTRACT FROM AUTHOR]

Abstract: Computer simulation of molecular systems enables structure–energy–function relationships of molecular processes to be described at the sub‐atomic, atomic, supra‐atomic, or supra‐molecular level. To interpret results of such simulations appropriately, the quality of the calculated properties must be evaluated. This depends on the way the simulations are performed and on the way they are validated by comparison to values Qexp of experimentally observable quantities Q. One must consider 1) the accuracy of Qexp, 2) the accuracy of the function Q(rN) used to calculate a Q‐value based on a molecular configuration rN of N particles, 3) the sensitivity of the function Q(rN) to the configuration rN, 4) the relative time scales of the simulation and experiment, 5) the degree to which the calculated and experimental properties are equivalent, and 6) the degree to which the system simulated matches the experimental conditions. Experimental data is limited in scope and generally corresponds to averages over both time and space. A critical analysis of the various factors influencing the apparent degree of (dis)agreement between simulations and experiment is presented and illustrated using examples from the literature. What can be done to enhance the validation of molecular simulation is also discussed. [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

E-cadherin is a transmembrane glycoprotein that facilitates inter-cellular adhesion in the epithelium. The ectodomain of the native structure is comprised of five repeated immunoglobulin-like domains. All E-cadherin crystal structures show the protein in one of three alternative conformations: a monomer, a strand-swapped trans homodimer and the so-called X-dimer, which is proposed to be a kinetic intermediate to forming the strand-swapped trans homodimer. However, previous studies have indicated that even once the trans strand-swapped dimer is formed, the complex is highly dynamic and the E-cadherin monomers may reorient relative to each other. Here, molecular dynamics simulations have been used to investigate the stability and conformational flexibility of the human E-cadherin trans strand-swapped dimer. In four independent, 100 ns simulations, the dimer moved away from the starting structure and converged to a previously unreported structure, which we call the Y-dimer. The Y-dimer was present for over 90% of the combined simulation time, suggesting that it represents a stable conformation of the E-cadherin dimer in solution. The Y-dimer conformation is stabilised by interactions present in both the trans strand-swapped dimer and X-dimer crystal structures, as well as additional interactions not found in any E-cadherin dimer crystal structures. The Y-dimer represents a previously unreported, stable conformation of the human E-cadherin trans strand-swapped dimer and suggests that the available crystal structures do not fully capture the conformations that the human E-cadherin trans homodimer adopts in solution. [ABSTRACT FROM AUTHOR]

The effect of varying the emitter concentration on the structural properties of an archetypal phosphorescent blend consisting of 4,4′-bis( N-carbazolyl)biphenyl and tris(2-phenylpyridyl)iridium(III) has been investigated using non-equilibrium molecular dynamics (MD) simulations that mimic the process of vacuum deposition. By comparison with reflectometry measurements, we show that the simulations provide an accurate model of the average density of such films. The emitter molecules were found not to be evenly distributed throughout film, but rather they can form networks that provide charge and/or energy migration pathways, even at emitter concentrations as low as ≈5 weight percent. At slightly higher concentrations, percolated networks form that span the entire system. While such networks would give improved charge transport, they could also lead to more non-radiative pathways for the emissive state and a resultant loss of efficiency. [ABSTRACT FROM AUTHOR]

The effect of varying the emitter concentration on the structural properties of an archetypal phosphorescent blend consisting of 4,4′-bis( N-carbazolyl)biphenyl and tris(2-phenylpyridyl)iridium(III) has been investigated using non-equilibrium molecular dynamics (MD) simulations that mimic the process of vacuum deposition. By comparison with reflectometry measurements, we show that the simulations provide an accurate model of the average density of such films. The emitter molecules were found not to be evenly distributed throughout film, but rather they can form networks that provide charge and/or energy migration pathways, even at emitter concentrations as low as ≈5 weight percent. At slightly higher concentrations, percolated networks form that span the entire system. While such networks would give improved charge transport, they could also lead to more non-radiative pathways for the emissive state and a resultant loss of efficiency. [ABSTRACT FROM AUTHOR]

During the past half century, the number and accuracy of experimental techniques that can deliver values of observables for biomolecular systems have been steadily increasing. The conversion of a measured value Qexp of an observable quantity Q into structural information is, however, a task beset with theoretical and practical problems: 1) insufficient or inaccurate values of Qexp, 2) inaccuracies in the function [ABSTRACT FROM AUTHOR]

Copyright of Angewandte Chemie is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

An interpretation of alternative crystal structures of the erythropoietin receptor, with and without ligand, led to the proposal of a scissor-like mechanism of activation. This model has been propagated in the literature and is still being used to interpret crystal structures of related type-I cytokine receptors. Here, we assess whether the model remains compatible with current knowledge on the family of type-I cytokine receptors, and consider whether the model, as initially presented, is truly supported by the crystal structures on which it was originally based. [ABSTRACT FROM AUTHOR]

Background and Purpose: The spider-venom peptide PcTx1 is the most potent and selective inhibitor of acid-sensing ion channel (ASIC) 1a. It has centrally acting analgesic activity and is neuroprotective in rodent models of ischaemic stroke. Understanding the molecular details of the PcTx1 : ASIC1a interaction should facilitate development of therapeutically useful ASIC1a modulators. Previously, we showed that several key pharmacophore residues of PcTx1 reside in a dynamic β-hairpin loop; conclusions confirmed by recent crystal structures of the complex formed between PcTx1 and chicken ASIC1 (cASIC1). Numerous peptide : channel contacts were observed in these crystal structures, but it remains unclear which of these are functionally important.Experimental Approach: We combined molecular dynamics (MD) simulations of the PcTx1 : cASIC1 complex with mutagenesis of PcTx1 and rat ASIC1a.Key Results: Crystal structures of the PcTx1 : cASIC1 complex indicated that 15 PcTx1 residues form a total of 57 pairwise intermolecular contacts (<5 Å) with 32 channel residues. MD simulations, however, suggested that about half of these interactions do not persist in solution. Mutation to alanine of only eight of 15 PcTx1 contact residues substantially altered ASIC1a inhibition by PcTx1. Our data reveal that many of the peptide-channel interactions observed in the PcTx1 : cASIC1 crystal structures are not important for PcTx1 inhibition of rat ASIC1a.Conclusions and Implications: We identified the atomic interactions that are critical for PcTx1 inhibition of ASIC1a. Our data highlight the value of combining structural information, MD and functional experiments to obtain detailed insight into the molecular basis of protein : protein interactions. [ABSTRACT FROM AUTHOR]

Starch is a complex branched glucose polymer whose branch molecular weight distribution (the chain-length distribution, CLD) influences nutritionally important properties such as digestion rate. Chain-stopping in starch biosynthesis is by starch branching enzyme (SBE). Site-directed mutagenesis was used to modify SBEIIa from Zea mays (mSBEIIa) to produce mutants, each differing in a single conserved amino-acid residue. Products at different times from in vitro branching were debranched and the time evolution of the CLD measured by size-exclusion chromatography. The results confirm that Tyr352, Glu513, and Ser349 are important for mSBEIIa activity while Arg456 is important for determining the position at which the linear glucan is cut. The mutant mSBEIIa enzymes have different activities and suggest the length of the transferred chain can be varied by mutation. The work shows analysis of the molecular weight distribution can yield information regarding the enzyme branching sites useful for development of plants yielding starch with improved functionality. [ABSTRACT FROM AUTHOR]

The role of small-angle X-ray scattering (SAXS) in structural biology is now well established, and its usefulness in combination with macromolecular crystallography is clear. However, the highly averaged SAXS data present a significant risk of over-interpretation to the unwary practitioner, and it can be challenging to frame SAXS results in a manner that maximises the reliability of the conclusions drawn. In this review, a series of recent examples are used to illustrate both the challenges for interpretation and approaches through which these can be overcome. [ABSTRACT FROM AUTHOR]

ABSTRACT Phox-homology (PX) domains target proteins to the organelles of the secretary and endocytic systems by binding to phosphatidylinositol phospholipids (PIPs). Among all the structures of PX domains that have been solved, only three have been solved in a complex with the main physiological ligand: PtdIns3 P. In this work, molecular dynamic simulations have been used to explore the structure and dynamics of the p40phox-PX domain and the SNX17-PX domain and their interaction with membrane-bound PtdIns3 P. In the simulations, both PX domains associated spontaneously with the membrane-bound PtdIns3 P and formed stable complexes. The interaction between the p40phox-PX domain and PtdIns3 P in the membrane was found to be similar to the crystal structure of the p40phox-PX-PtdIns3 P complex that is available. The interaction between the SNX17-PX domain and PtdIns3 P was similar to that observed in the p40phox-PX-PtdIns3 P complex; however, some residues adopted different orientations. The simulations also showed that nonspecific interactions between the β1- β2 loop and the membrane play an important role in the interaction of membrane bound PtdIns3 P and different PX domains. The behaviour of unbound PtdIns3 P within a 2-oleoyl-1-palmitoyl- sn-glycero-3-phosphocholine (POPC) membrane environment was also examined and compared to the available experimental data and simulation studies of related molecules. Proteins 2014; 82:2332-2342. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

ATP Binding Cassette (ABC) transporters couple the binding and hydrolysis of ATP to the transport of substrate molecules across the membrane. The mechanism by which ATP binding and/or hydrolysis drives the conformational changes associated with substrate transport has not yet been characterized fully. Here, changes in the conformation of the ABC export protein P-glycoprotein on ATP binding are examined in a series of molecular dynamics simulations. When one molecule of ATP is placed at the ATP binding site associated with each of the two nucleotide binding domains (NBDs), the membrane-embedded P-glycoprotein crystal structure adopts two distinct metastable conformations. In one, each ATP molecule interacts primarily with the Walker A motif of the corresponding NBD. In the other, the ATP molecules interacts with both Walker A motif of one NBD and the Signature motif of the opposite NBD inducing the partial dimerization of the NBDs. This interaction is more extensive in one of the two ATP binding site, leading to an asymmetric structure. The overall conformation of the transmembrane domains is not altered in either of these metastable states, indicating that the conformational changes associated with ATP binding observed in the simulations in the absence of substrate do not lead to the outward-facing conformation and thus would be insufficient in themselves to drive transport. Nevertheless, the metastable intermediate ATP-bound conformations observed are compatible with a wide range of experimental cross-linking data demonstrating the simulations do capture physiologically important conformations. Analysis of the interaction between ATP and its cofactor Mg2+ with each NBD indicates that the coordination of ATP and Mg2+ differs between the two NBDs. The role structural asymmetry may play in ATP binding and hydrolysis is discussed. Furthermore, we demonstrate that our results are not heavily influenced by the crystal structure chosen for initiation of the simulations. [ABSTRACT FROM AUTHOR]

The antibiotic vancomycin targets lipid II, blocking cell wall synthesis in Gram-positive bacteria. Despite extensive study, questions remain regarding how it recognizes its primary ligand and what is the most biologically relevant form of vancomycin. In this study, molecular dynamics simulation techniques have been used to examine the process of ligand binding and dimerization of vancomycin. Starting from one or more vancomycin monomers in solution, together with different peptide ligands derived from lipid II, the simulations predict the structures of the ligated monomeric and dimeric complexes to within 0.1 nm rmsd of the structures determined experimentally. The simulations reproduce the conformation transitions observed by NMR and suggest that proposed differences between the crystal structure and the solution structure are an artifact of the way the NMR data has been interpreted in terms of a structural model. The spontaneous formation of both back-to-back and face-to-face dimers was observed in the simulations. This has allowed a detailed analysis of the origin of the cooperatively between ligand binding and dimerization and suggests that the formation of face-to-face dimers could be functionally significant. The work also highlights the possible role of structural water in stabilizing the vancomycin ligand complex and its role in the manifestation of vancomycin resistance. [ABSTRACT FROM AUTHOR]

The efficiency of using a variant of Hamiltonian replica-exchange molecular dynamics (Chaperone H-replica-exchange molecular dynamics [CH-REMD]) for the refinement of protein structural models generated de novo is investigated. In CH-REMD, the interaction between the protein and its environment, specifically, the electrostatic interaction between the protein and the solvating water, is varied leading to cycles of partial unfolding and refolding mimicking some aspects of folding chaperones. In 10 of the 15 cases examined, the CH-REMD approach sampled structures in which the root-mean-square deviation (RMSD) of secondary structure elements (SSE-RMSD) with respect to the experimental structure was more than 1.0 Å lower than the initial de novo model. In 14 of the 15 cases, the improvement was more than 0.5 Å. The ability of three different statistical potentials to identify near-native conformations was also examined. Little correlation between the SSE-RMSD of the sampled structures with respect to the experimental structure and any of the scoring functions tested was found. The most effective scoring function tested was the DFIRE potential. Using the DFIRE potential, the SSE-RMSD of the best scoring structures was on average 0.3 Å lower than the initial model. Overall the work demonstrates that targeted enhanced-sampling techniques such as CH-REMD can lead to the systematic refinement of protein structural models generated de novo but that improved potentials for the identification of near-native structures are still needed. Proteins 2012; © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Despite its central role in structure based drug design the determination of the binding mode (position, orientation and conformation in addition to protonation and tautomeric states) of small heteromolecular ligands in protein:ligand complexes based on medium resolution X-ray diffraction data is highly challenging. In this perspective we demonstrate how a combination of molecular dynamics simulations and free energy (FE) calculations can be used to correct and identify thermodynamically stable binding modes of ligands in X-ray crystal complexes. The consequences of inappropriate ligand structure, force field and the absence of electrostatics during X-ray refinement are highlighted. The implications of such uncertainties and errors for the validation of virtual screening and fragment-based drug design based on high throughput X-ray crystallography are discussed with possible solutions and guidelines. [ABSTRACT FROM AUTHOR]

Methods to compute free energy differences between different states of a molecular system are reviewed with the aim of identifying their basic ingredients and their utility when applied in practice to biomolecular systems. A free energy calculation is comprised of three basic components: (i) a suitable model or Hamiltonian, (ii) a sampling protocol with which one can generate a representative ensemble of molecular configurations, and (iii) an estimator of the free energy difference itself. Alternative sampling protocols can be distinguished according to whether one or more states are to be sampled. In cases where only a single state is considered, six alternative techniques could be distinguished: (i) changing the dynamics, (ii) deforming the energy surface, (iii) extending the dimensionality, (iv) perturbing the forces, (v) reducing the number of degrees of freedom, and (vi) multi-copy approaches. In cases where multiple states are to be sampled, the three primary techniques are staging, importance sampling, and adiabatic decoupling. Estimators of the free energy can be classified as global methods that either count the number of times a given state is sampled or use energy differences. Or, they can be classified as local methods that either make use of the force or are based on transition probabilities. Finally, this overview of the available techniques and how they can be best used in a practical context is aimed at helping the reader choose the most appropriate combination of approaches for the biomolecular system, Hamiltonian and free energy difference of interest. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

A new force field for the simulation of dipalmitoylphosphatidylcholine (DPPC) in the liquid-crystalline, fluid phase at zero surface tension is presented. The structure of the bilayer with the area per lipid (0.629 nm2; experiment 0.629–0.64 nm2), the volume per lipid (1.226 nm3; experiment 1.229–1.232 nm3), and the ordering of the palmitoyl chains (order parameters) are all in very good agreement with experiment. Experimental electron density profiles are well reproduced in particular with regard to the penetration of water into the bilayer. The force field was further validated by simulating the spontaneous assembly of DPPC into a bilayer in water. Notably, the timescale on which membrane sealing was observed using this model appears closer to the timescales for membrane resealing suggested by electroporation experiments than previous simulations using existing models. © 2009 Wiley Periodicals, Inc. J Comput Chem, 2010 [ABSTRACT FROM AUTHOR]

Atomistic molecular dynamics simulations have been used to investigate the conformational changes associated with the binding of human growth hormone (hGH) to the extracellular domains (ECD) of the human growth hormone receptor (hGHR), thereby shedding light on the mechanism of activation. It is shown that the removal of hGH from the hormone-bound receptor complex results in a counter-clockwise rotation of the twosubunits relative to each other by 30°-64° (average 45° ± 14°), in close agreement in terms of both the magnitude and direction of the rotation with that proposed based on mutagenesis experiments. In addition to providing evidence to support a rotational activation mechanism, the simulations have enabled the nature of the interaction interfaces in both the cytokine-bound and unliganded hGHR states to be analyzed in detail. Proteins 2010. © 2009 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

When estimating binding affinities of a ligand, which can exists in multiple forms, for a target molecule, one must consider all possible competing equilibria. Here, a method is presented that estimates the contribution of the protonation equilibria of a ligand in solution to the measured or calculated binding affinity. The method yields a correction to binding constants that are based on the total concentration of inhibitor (the sum of all ionized forms of the inhibitor in solution) to account for the complexed form of the inhibitor only. The method is applied to the calculation of the difference in binding affinity of two inhibitors, 2-phosphoglycolate (PGA) and its phoshonate analog 3-phosphonopropionate (3PP), for the glycolytic enzyme triosephosphate isomerase. Both inhibitors have three titrating sites and exist in solution as a mixture of different forms. In this case the form that actually binds to the enzyme is present at relative low concentrations. The contributions of the alternative forms to the difference in binding energies is estimated by means of molecular dynamics simulations and corrections. The inhibitors undergo a p Ka shift upon binding that is estimated by ab initio calculations. An interesting finding is that the affinity difference of the two inhibitors is not due to different interactions in the active site of the enzyme, but rather due to the difference in the solvation properties of the inhibitors. Protein 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The free-energy landscape of a small protein, the FBP 28 WW domain, has been explored using molecular dynamics (MD) simulations with alternative descriptions of the molecule. The molecular models used range from coarse-grained to all-atom with either an implicit or explicit treatment of the solvent. Sampling of conformation space was performed using both conventional and temperature-replica exchange MD simulations. Experimental chemical shifts and NOEs were used to validate the simulations, and experimental φ values both for validation and as restraints. This combination of different approaches has provided insight into the free energy landscape and barriers encountered by the protein during folding and enabled the characterization of native, denatured and transition states which are compatible with the available experimental data. All the molecular models used stabilize well defined native and denatured basins; however, the degree of agreement with the available experimental data varies. While the most detailed, explicit solvent model predicts the data reasonably accurately, it does not fold despite a simulation time 10 times that of the experimental folding time. The less detailed models performed poorly relative to the explicit solvent model: an implicit solvent model stabilizes a ground state which differs from the experimental native state, and a structure-based model underestimates the size of the barrier between the two states. The use of experimental φ values both as restraints, and to extract structures from unfolding simulations, result in conformations which, although not necessarily true transition states, appear to share the geometrical characteristics of transition state structures. In addition to characterizing the native, transition and denatured states of this particular system in this work, the advantages and limitations of using varying levels of representation are discussed. © 2008 Wiley Periodicals, Inc. J Comput Chem, 2009 [ABSTRACT FROM AUTHOR]

In 1968, Fröhlich showed that a driven set of oscillators can condense with nearly all of the supplied energy activating the vibrational mode of lowest frequency. This is a remarkable property usually compared with Bose-Einstein condensation, superconductivity, lasing, and other unique phenomena involving macroscopic quantum coherence. However, despite intense research, no unambiguous example has been documented. We determine the most likely experimental signaturesof Fröhlich condensation and show that they are signif icant features remote from the extraordinary properties normally envisaged. Fröhlich condensates are classified into 3 types: weak condensates in which profound effects on chemical kinetics are possible, strong condensates in which an extremely large amount of energy is channeled into 1 vibrational mode, and coherent condensates in which this energy is placed in a single quantum state. Coherent condensates are shown to involve extremely large energies, to not be produced by the Wu-Austin dynamical Hamiltonian that provides the simplest depiction of Fröhlich condensates formed using mechanically supplied energy, and to be extremely fragile. They are inaccessible in a biological environment. Hence the Penrose-Hameroff orchestrated objective-reduction model and related theories for cognitive function that embody coherent Fröhlich condensation as an essential element are untenable. Weak condensates, however, may have profound effects on chemical and enzyme kinetics, and may be produced from biochemical energy or from radio frequency, microwave, or terahertz radiation. Pokorny's observed 8.085-MHz microtubulin resonance is identified as a possible candidate, with microwave reactors (green chemistry) and terahertz medicine appearing as other feasible sources. [ABSTRACT FROM AUTHOR]

The purple membrane (PM) is a specialized membrane patch found in halophilic archaea, containing the photoreceptor bacteriorhodopsin (bR). It is long known that calcium ions bind to the PM, but their position and role remain elusive to date. Molecular dynamics simulations in conjunction with a highly detailed model of the PM have been used to investigate the stability of calcium ions placed at three proposed cation binding sites within bR, one near the Schiff base, one in the region of the proton release group, and one near Glu9. The simulations suggest that, of the sites investigated, the binding of calcium ions was most likely at the proton release group. Binding in the region of the Schiff base, while possible, was associated with significant changes in local geometry. Calcium ions placed near Glu9 in the interior of bR (simultaneously to a Ca2+ near the Schiff base and another one near the Glu194-Glu204 site) were not stable. The results obtained are discussed in relation to recent experimental observations and theoretical considerations. Proteins 2009. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

A protocol is presented for the global refinement of homology models of proteins. It combines the advantages of temperature-based replica-exchange molecular dynamics (REMD) for conformational sampling and the use of statistical potentials for model selection. The protocol was tested using 21 models. Of these 14 were models of 10 small proteins for which high-resolution crystal structures were available, the remainder were targets of the recent CASPR exercise. It was found that REMD in combination with currently available force fields could sample near-native conformational states starting from high-quality homology models. Conformations in which the backbone RMSD of secondary structure elements (SSE-RMSD) was lower than the starting value by 0.5-1.0 Å were found for 15 out of the 21 cases (average 0.82 Å). Furthermore, when a simple scoring function consisting of two statistical potentials was used to rank the structures, one or more structures with SSE-RMSD of at least 0.2 Å lower than the starting value was found among the five best ranked structures in 11 out of the 21 cases. The average improvement in SSE-RMSD for the best models was 0.42 Å. However, none of the scoring functions tested identified the structures with the lowest SSE-RMSD as the best models although all identified the native conformation as the one with lowest energy. This suggests that while the proposed protocol proved effective for the refinement of high-quality models of small proteins scoring functions remain one of the major limiting factors in structure refinement. This and other aspects by which the methodology could be further improved are discussed. Proteins 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The Death Receptor 5 (DR5), a member of tumor necrosis factor receptor (TNFR) superfamily of receptors, triggers apoptosis (programmed cell death) when stimulated by its tridentate ligand TRAIL. Until recently it was generally assumed that the activation of DR5 resulted from the recruitment of three independent receptor units, leading to the trimerization of intracellular domains. However, there is mounting evidence to suggest that, in the absence of ligand, such cytokine receptors primarily reside as preformed complexes. In this work, molecular dynamics simulations of the TRAIL-DR5 complex, the unbound receptor trimer and individual receptor monomers are compared to gain insight in the mechanism of activation. The results suggest that, in the absence of TRAIL, DR5 has a strong propensity to self-associate and that this is primarily mediated through interactions of the membrane proximal domains. The association of the free receptors leads to a loss of the threefold symmetry found within the receptor-ligand complex. The simulations suggest that the primary role of TRAIL is to induce threefold-symmetry within the DR5 complex and to constrain the receptor to a specific conformation. The implications of this in terms of the mechanism by which the receptor switches from an inactive to an active state are discussed. Proteins 2008. © 2007 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

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Hydrophobins are small (∼100 aa) proteins that have an important role in the growth and development of mycelial fungi. They are surface active and, after secretion by the fungi, self-assemble into amphipathic membranes at hydrophobic/hydrophilic interfaces, reversing the hydrophobicity of the surface. In this study, molecular dynamics simulation techniques have been used to model the process by which a specific class I hydrophobin, SC3, binds to a range of hydrophobic/hydrophilic interfaces. The structure of SC3 used in this investigation was modeled based on the crystal structure of the class II hydrophobin HFBII using the assumption that the disulfide pairings of the eight conserved cysteine residues are maintained. The proposed model for SC3 in aqueous solution is compact and globular containing primarily β-strand and coil structures. The behavior of this model of SC3 was investigated at an air/water, an oil/water, and a hydrophobic solid/water interface. It was found that SC3 preferentially binds to the interfaces via the loop region between the third and fourth cysteine residues and that binding is associated with an increase in α-helix formation in qualitative agreement with experiment. Based on a combination of the available experiment data and the current simulation studies, we propose a possible model for SC3 self-assembly on a hydrophobic solid/water interface. Proteins 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Bacterial chaperonin, GroEL, together with its co-chaperonin, GroES, facilitates the folding of a variety of polypeptides. Experiments suggest that GroEL stimulates protein folding by multiple cycles of binding and release. Misfolded proteins first bind to an exposed hydrophobic surface on GroEL. GroES then encapsulates the substrate and triggers its release into the central cavity of the GroEL/ES complex for folding. In this work, we investigate the possibility to facilitate protein folding in molecular dynamics simulations by mimicking the effects of GroEL/ES namely, repeated binding and release, together with spatial confinement. During the binding stage, the (metastable) partially folded proteins are allowed to attach spontaneously to a hydrophobic surface within the simulation box. This destabilizes the structures, which are then transferred into a spatially confined cavity for folding. The approach has been tested by attempting to refine protein structural models generated using the ROSETTA procedure for ab initio structure prediction. Dramatic improvements in regard to the deviation of protein models from the corresponding experimental structures were observed. The results suggest that the primary effects of the GroEL/ES system can be mimicked in a simple coarse-grained manner and be used to facilitate protein folding in molecular dynamics simulations. Furthermore, the results support the assumption that the spatial confinement in GroEL/ES assists the folding of encapsulated proteins. [ABSTRACT FROM AUTHOR]

The effect of the box shape on the dynamic behavior of proteins simulated under periodic boundary conditions is evaluated. In particular, the influence of simulation boxes defined by the near-densest lattice packing (NDLP) in conjunction with rotational constraints is compared to that of standard box types without these constraints. Three different proteins of varying size, shape, and secondary structure content were examined in the study. The statistical significance of differences in RMSD, radius of gyration, solvent-accessible surface, number of hydrogen bonds, and secondary structure content between proteins, box types, and the application or not of rotational constraints has been assessed. Furthermore, the differences in the collective modes for each protein between different boxes and the application or not of rotational constraints have been examined. In total 105 simulations were performed, and the results compared using a three-way multivariate analysis of variance (MANOVA) for properties derived from the trajectories and a three-way univariate analysis of variance (ANOVA) for collective modes. It is shown that application of roto-translational constraints does not have a statistically significant effect on the results obtained from the different simulations. However, the choice of simulation box was found to have a small (5–10%), but statistically significant effect on the behavior of two of the three proteins included in the study. © 2005 Wiley Periodicals, Inc. J Comput Chem 27: 316–325, 2006 [ABSTRACT FROM AUTHOR]