Shun Sakuraba

Ermod: fast and versatile computation software for solvation free energy with approximate theory of solutions.

ERmod is a software package to efficiently and approximately compute the solvation free energy using the method of energy representation. Molecular simulation is to be conducted at two condensed‐phase systems of the solution of interest and the reference solvent with test‐particle insertion of the solute. The subprogram ermod in ERmod then provides a set of energy distribution functions from the simulation trajectories, and another subprogram slvfe determines the solvation free energy from the distribution functions through an approximate functional. This article describes the design and implementation of ERmod, and illustrates its performance in solvent water for two organic solutes and two protein solutes. Actually, the free‐energy computation with ERmod is not restricted to the solvation in homogeneous medium such as fluid and polymer and can treat the binding into weakly ordered system with nano‐inhomogeneity such as micelle and lipid membrane. ERmod is available on web at http://sourceforge.net/projects/ermod.

Evaluation of protein-protein docking model structures using all-atom molecular dynamics simulations combined with the solution theory in the energy representation.

We propose a method to evaluate binding free energy differences among distinct protein-protein complex model structures through all-atom molecular dynamics simulations in explicit water using the solution theory in the energy representation. Complex model structures are generated from a pair of monomeric structures using the rigid-body docking program ZDOCK. After structure refinement by side chain optimization and all-atom molecular dynamics simulations in explicit water, complex models are evaluated based on the sum of their conformational and solvation free energies, the latter calculated from the energy distribution functions obtained from relatively short molecular dynamics simulations of the complex in water and of pure water based on the solution theory in the energy representation. We examined protein-protein complex model structures of two protein-protein complex systems, bovine trypsin/CMTI-1 squash inhibitor (PDB ID: 1PPE) and RNase SA/barstar (PDB ID: 1AY7), for which both complex and monomer structures were determined experimentally. For each system, we calculated the energies for the crystal complex structure and twelve generated model structures including the model most similar to the crystal structure and very different from it. In both systems, the sum of the conformational and solvation free energies tended to be lower for the structure similar to the crystal. We concluded that our energy calculation method is useful for selecting low energy complex models similar to the crystal structure from among a set of generated models.

Interaction-component analysis of the hydration and urea effects on cytochrome c

Energetics was analyzed for cytochrome c in pure-water solvent and in a urea-water mixed solvent to elucidate the solvation effect in the structural variation of the protein. The solvation free energy was computed through all-atom molecular dynamics simulation combined with the solution theory in the energy representation, and its correlations were examined over sets of protein structures against the electrostatic and van der Waals components in the average interaction energy of the protein with the solvent and the excluded-volume component in the solvation free energy. It was observed in pure-water solvent that the solvation free energy varies in parallel to the electrostatic component with minor roles played by the van der Waals and excluded-volume components. The effect of urea on protein structure was then investigated in terms of the free-energy change upon transfer of the protein solute from pure-water solvent to the urea-water mixed solvent. The decomposition of the transfer free energy into the contributions from urea and water showed that the urea contribution is partially canceled by the water contribution and governs the total free energy of transfer. When correlated against the change in the solute-solvent interaction energy upon transfer and the corresponding changes in the electrostatic, van der Waals, and excluded-volume components, the transfer free energy exhibited strong correlations with the total change in the solute-solvent energy and its van der Waals component. The solute-solvent energy was decomposed into the contributions from the protein backbone and side chain, furthermore, and neither of the contributions was seen to be decisive in the correlation to the transfer free energy.

Detecting coupled collective motions in protein by independent subspace analysis

Protein dynamics evolves in a high-dimensional space, comprising aharmonic, strongly correlated motional modes. Such correlation often plays an important role in analyzing protein function. In order to identify significantly correlated collective motions, here we employ independent subspace analysis based on the subspace joint approximate diagonalization of eigenmatrices algorithm for the analysis of molecular dynamics (MD) simulation trajectories. From the 100 ns MD simulation of T4 lysozyme, we extract several independent subspaces in each of which collective modes are significantly correlated, and identify the other modes as independent. This method successfully detects the modes along which long-tailed non-Gaussian probability distributions are obtained. Based on the time cross-correlation analysis, we identified a series of events among domain motions and more localized motions in the protein, indicating the connection between the functionally relevant phenomena which have been independently revealed by experiments.

NMR-NOE and MD simulation study on phospholipid membranes: dependence on membrane diameter and multiple time scale dynamics.

Motional correlation times between the hydrophilic and hydrophobic terminal groups in lipid membranes are studied over a wide range of curvatures using the solution-state (1)H NMR-nuclear Overhauser effect (NOE) and molecular dynamics (MD) simulation. To enable (1)H NMR-NOE measurements for large vesicles, the transient NOE method is combined with the spin-echo method, and is successfully applied to a micelle of 1-palmitoyl-lysophosphatidylcholine (PaLPC) with diameter of 5 nm and to vesicles of dipalmitoylphosphatidylcholine (DPPC) with diameters ranging from 30 to 800 nm. It is found that the NOE intensity increases with the diameter up to ∼100 nm, and the model membrane is considered planar on the molecular level beyond ∼100 nm. While the NOE between the hydrophilic terminal and hydrophobic terminal methyl groups is absent for the micelle, its intensity is comparable to that for the neighboring group for vesicles with larger diameters. The origin of NOE signals between distant sites is analyzed by MD simulations of PaLPC micelles and DPPC planar bilayers. The slow relaxation is shown to yield an observable NOE signal even for the hydrophilic and hydrophobic terminal sites. Since the information on distance and dynamics cannot be separated in the experimental NOE alone, the correlation time in large vesicles is determined by combining the experimental NOE intensity and MD-based distance distribution. For large vesicles, the correlation time is found to vary by 2 orders of magnitude over the proton sites. This study shows that NOE provides dynamic information on large vesicles when combined with MD, which provides structural information.

H3 Histone Tail Conformation within the Nucleosome and the Impact of K14 Acetylation Studied Using Enhanced Sampling Simulation

Acetylation of lysine residues in histone tails is associated with gene transcription. Because histone tails are structurally flexible and intrinsically disordered, it is difficult to experimentally determine the tail conformations and the impact of acetylation. In this work, we performed simulations to sample H3 tail conformations with and without acetylation. The results show that irrespective of the presence or absence of the acetylation, the H3 tail remains in contact with the DNA and assumes an α-helix structure in some regions. Acetylation slightly weakened the interaction between the tail and DNA and enhanced α-helix formation, resulting in a more compact tail conformation. We inferred that this compaction induces unwrapping and exposure of the linker DNA, enabling DNA-binding proteins (e.g., transcription factors) to bind to their target sequences. In addition, our simulation also showed that acetylated lysine was more often exposed to the solvent, which is consistent with the fact that acetylation functions as a post-translational modification recognition site marker.

Adaptive lambda square dynamics simulation: an efficient conformational sampling method for biomolecules.

A novel, efficient sampling method for biomolecules is proposed. The partial multicanonical molecular dynamics (McMD) was recently developed as a method that improved generalized ensemble (GE) methods to focus sampling only on a part of a system (GEPS); however, it was not tested well. We found that partial McMD did not work well for polylysine decapeptide and gave significantly worse sampling efficiency than a conventional GE. Herein, we elucidate the fundamental reason for this and propose a novel GEPS, adaptive lambda square dynamics (ALSD), which can resolve the problem faced when using partial McMD. We demonstrate that ALSD greatly increases the sampling efficiency over a conventional GE. We believe that ALSD is an effective method and is applicable to the conformational sampling of larger and more complicated biomolecule systems.

Distribution-function approach to free energy computation

Connections are explored between the free energy difference of two systems and the microscopic distribution functions of the energy difference. On the basis of a rigorous relationship between the energy distribution functions and the free energy, the scheme of error minimization is introduced to derive accurate and simple methods of free energy computation. A set of distribution-function approaches are then examined against model systems, and the newly derived methods exhibit state-of-art performance. It is shown that the notion of error minimization is powerful to improve the free energy calculation using distribution functions.

A theoretical study of the two binding modes between lysozyme and tri-NAG with an explicit solvent model based on the fragment molecular orbital method

To examine the stabilities and binding characteristics, fragment molecular orbital (FMO) calculations were performed for the two binding modes of hen egg-white lysozyme with tri-N-acetyl-D-glucosamine (tri-NAG). Solvent effects were considered using an explicit solvent model. For comparison with the computational results, we experimentally determined the enthalpic contribution of the binding free-energy. Our calculations showed that the binding mode observed by X-ray analysis was more stable than the other binding mode by -6.2 kcal mol(-1), where it was found that the interaction of protein with solvent molecules was crucial for this stability. The amplitude of this energy difference was of the same order as the experimental enthalpic contribution. Our detailed analysis using the energies divided into each residue was also consistent with a previous mutant study. In addition, the electron density analysis showed that the formal charge of the lysozyme (+8.0 e) was reduced to +5.16 e by charge transfer with solvent molecules.

Multiple Markov transition matrix method: obtaining the stationary probability distribution from multiple simulations.

We herein propose the multiple Markov transition matrix method (MMMM), an algorithm by which to estimate the stationary probability distribution from independent multiple molecular dynamics simulations with different Hamiltonians. Applications to the potential of mean force calculation in combination with the umbrella sampling method are presented. First, the performance of the MMMM is examined in the case of butane. Compared with the weighted histogram analysis method (WHAM), the MMMM has an advantage with respect to the reasonable evaluation of the stationary probability distribution even from nonequilibrium trajectories. This method is then applied to Met‐enkephalin nonequilibrium simulation.