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Computing membrane-AQP5-phosphatidylserine binding affinities with hybrid steered molecular dynamics approach.

ABSTRACT: In order to elucidate how phosphatidylserine (PS6) interacts with AQP5 in a cell membrane, we developed a hybrid steered molecular dynamics (hSMD) method that involved: (1) Simultaneously steering two centers of mass of two selected segments of the ligand, and (2) equilibrating the ligand-protein complex with and without biasing the system. Validating hSMD, we first studied vascular endothelial growth factor receptor 1 (VEGFR1) in complex with N-(4-Chlorophenyl)-2-((pyridin-4-ylmethyl)amino)benzamide (8ST), for which the binding energy is known from in vitro experiments. In this study, our computed binding energy well agreed with the experimental value. Knowing the accuracy of this hSMD method, we applied it to the AQP5-lipid-bilayer system to answer an outstanding question relevant to AQP5's physiological function: Will the PS6, a lipid having a single long hydrocarbon tail that was found in the central pore of the AQP5 tetramer crystal, actually bind to and inhibit AQP5's central pore under near-physiological conditions, namely, when AQP5 tetramer is embedded in a lipid bilayer? We found, in silico, using the CHARMM 36 force field, that binding PS6 to AQP5 was a factor of 3 million weaker than "binding" it in the lipid bilayer. This suggests that AQP5's central pore will not be inhibited by PS6 or a similar lipid in a physiological environment.

SUBMITTER: Chen LY

PROVIDER: S-EPMC4523441 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Computing membrane-AQP5-phosphatidylserine binding affinities with hybrid steered molecular dynamics approach.

Chen Liao Y LY

Molecular membrane biology 20150508 1

In order to elucidate how phosphatidylserine (PS6) interacts with AQP5 in a cell membrane, we developed a hybrid steered molecular dynamics (hSMD) method that involved: (1) Simultaneously steering two centers of mass of two selected segments of the ligand, and (2) equilibrating the ligand-protein complex with and without biasing the system. Validating hSMD, we first studied vascular endothelial growth factor receptor 1 (VEGFR1) in complex with N-(4-Chlorophenyl)-2-((pyridin-4-ylmethyl)amino)benz ...[more]

PMID: 25955791

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Project description:Computing protein-protein association affinities is one of the fundamental challenges in computational biophysics/biochemistry. The overwhelming amount of statistics in the phase space of very high dimensions cannot be sufficiently sampled even with today's high-performance computing power. In this article, we extend a potential of mean force (PMF)-based approach, the hybrid steered molecular dynamics (hSMD) approach we developed for ligand-protein binding, to protein-protein association problems. For a protein complex consisting of two protomers, P1 and P2, we choose m (≥3) segments of P1 whose m centers of mass are to be steered in a chosen direction and n (≥3) segments of P2 whose n centers of mass are to be steered in the opposite direction. The coordinates of these m + n centers constitute a phase space of 3(m + n) dimensions (3(m + n)D). All other degrees of freedom of the proteins, ligands, solvents, and solutes are freely subject to the stochastic dynamics of the all-atom model system. Conducting SMD along a line in this phase space, we obtain the 3(m + n)D PMF difference between two chosen states: one single state in the associated state ensemble and one single state in the dissociated state ensemble. This PMF difference is the first of four contributors to the protein-protein association energy. The second contributor is the 3(m + n - 1)D partial partition in the associated state accounting for the rotations and fluctuations of the (m + n - 1) centers while fixing one of the m + n centers of the P1-P2 complex. The two other contributors are the 3(m - 1)D partial partition of P1 and the 3(n - 1)D partial partition of P2 accounting for the rotations and fluctuations of their m - 1 or n - 1 centers while fixing one of the m/n centers of P1/P2 in the dissociated state. Each of these three partial partitions can be factored exactly into a 6D partial partition in multiplication with a remaining factor accounting for the small fluctuations while fixing three of the centers of P1, P2, or the P1-P2 complex, respectively. These small fluctuations can be well-approximated as Gaussian, and every 6D partition can be reduced in an exact manner to three problems of 1D sampling, counting the rotations and fluctuations around one of the centers as being fixed. We implement this hSMD approach to the Ras-RalGDS complex, choosing three centers on RalGDS and three on Ras (m = n = 3). At a computing cost of about 71.6 wall-clock hours using 400 computing cores in parallel, we obtained the association energy, -9.2 ± 1.9 kcal/mol on the basis of CHARMM 36 parameters, which well agrees with the experimental data, -8.4 ± 0.2 kcal/mol.

Project description:Computing the free energy of binding a ligand to a protein is a difficult task of essential importance for which purpose various theoretical/computational approaches have been pursued. In this paper, we develop a hybrid steered molecular dynamics (hSMD) method capable of resolving one ligand–protein complex within a few wall-clock days with high enough accuracy to compare with the experimental data. This hSMD approach is based on the relationship between the binding affinity and the potential of mean force (PMF) in the established literature. It involves simultaneously steering n (n = 1, 2, 3, ...) centers of mass of n selected segments of the ligand using n springs of infinite stiffness. Steering the ligand from a single initial state chosen from the bound state ensemble to the corresponding dissociated state, disallowing any fluctuations of the pulling centers along the way, one can determine a 3n-dimensional PMF curve connecting the two states by sampling a small number of forward and reverse pulling paths. This PMF constitutes a large but not the sole contribution to the binding free energy. Two other contributors are (1) the partial partition function containing the equilibrium fluctuations of the ligand at the binding site and the deviation of the initial state from the PMF minimum and (2) the partial partition function containing rotation and fluctuations of the ligand around one of the pulling centers that is fixed at a position far from the protein. We implement this hSMD approach for two ligand–protein complexes whose structures were determined and whose binding affinities were measured experimentally: caprylic acid binding to bovine ?-lactoglobulin and glutathione binding to Schistosoma japonicum glutathione S-transferase tyrosine 7 to phenylalanine mutant. Our computed binding affinities agree with the experimental data within a factor of 1.5. The total time of computation for these two all-atom model systems (consisting of 96K and 114K atoms, respectively) was less than one wall-clock week using 512 cores (32 Xeon E5-2680 processors).

Project description:Computing the ligand-protein binding affinity (or the Gibbs free energy) with chemical accuracy has long been a challenge for which many methods/approaches have been developed and refined with various successful applications. False positives and, even more harmful, false negatives have been and still are a common occurrence in practical applications. Inevitable in all approaches are the errors in the force field parameters we obtain from quantum mechanical computation and/or empirical fittings for the intra- and inter-molecular interactions. These errors propagate to the final results of the computed binding affinities even if we were able to perfectly implement the statistical mechanics of all the processes relevant to a given problem. And they are actually amplified to various degrees even in the mature, sophisticated computational approaches. In particular, the free energy perturbation (alchemical) approaches amplify the errors in the force field parameters because they rely on extracting the small differences between similarly large numbers. In this paper, we develop a hybrid steered molecular dynamics (hSMD) approach to the difficult binding problems of a ligand buried deep inside a protein. Sampling the transition along a physical (not alchemical) dissociation path of opening up the binding cavity---pulling out the ligand---closing back the cavity, we can avoid the problem of error amplifications by not relying on small differences between similar numbers. We tested this new form of hSMD on retinol inside cellular retinol-binding protein 1 and three cases of a ligand (a benzylacetate, a 2-nitrothiophene, and a benzene) inside a T4 lysozyme L99A/M102Q(H) double mutant. In all cases, we obtained binding free energies in close agreement with the experimentally measured values. This indicates that the force field parameters we employed are accurate and that hSMD (a brute force, unsophisticated approach) is free from the problem of error amplification suffered by many sophisticated approaches in the literature.

Project description:HIV-1 reverse transcriptase (RT) is the primary target for anti-AIDS chemotherapy. Nonnucleoside RT inhibitors (NNRTIs) are very potent and most promising anti-AIDS drugs that specifically inhibit HIV-1 RT. The binding and unbinding processes of alpha-APA, an NNRTI, have been studied using nanosecond conventional molecular dynamics and steered molecular dynamics simulations. The simulation results show that the unbinding process of alpha-APA consists of three phases based on the position of alpha-APA in relation to the entrance of the binding pocket. When alpha-APA is bound in the binding pocket, the hydrophobic interactions between HIV-1 RT and alpha-APA dominate the binding; however, the hydrophilic interactions (both direct and water-bridged hydrogen bonds) also contribute to the stabilizing forces. Whereas Tyr-181 makes significant hydrophobic interactions with alpha-APA, Tyr-188 forms a strong hydrogen bond with the acylamino group (N14) of alpha-APA. These two residues have very flexible side chains and appear to act as two "flexible clamps" discouraging alpha-APA to dissociate from the binding pocket. At the pocket entrance, two relatively inflexible residues, Val-179 and Leu-100, gauge the openness of the entrance and form the bottleneck of the inhibitor-unbinding pathway. Two special water molecules at the pocket entrance appear to play important roles in inhibitor recognition of binding and unbinding. These water molecules form water bridges between the polar groups of the inhibitor and the residues around the entrance, and between the polar groups of the inhibitor themselves. The water-bridged interactions not only induce the inhibitor to adopt an energetically favorable conformation so the inhibitor can pass through the pocket entrance, but also stabilize the binding of the inhibitor in the pocket to prevent the inhibitor's dissociation. The complementary steered molecular dynamics and conventional molecular dynamics simulation results strongly support the hypothesis that NNRTIs inhibit HIV-1 RT polymerization activity by enlarging the DNA-binding cleft and restricting the flexibility and mobility of the p66 thumb subdomain that are believed to be essential during DNA translocation and polymerization.

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Computing membrane-AQP5-phosphatidylserine binding affinities with hybrid steered molecular dynamics approach.

Publications

Computing membrane-AQP5-phosphatidylserine binding affinities with hybrid steered molecular dynamics approach.

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