Chigusa Kobayashi

Mechanism of fast proton transfer in ice: Potential energy surface and reaction coordinate analyses

The mechanism of proton transfer in ice is investigated theoretically by examining the potential energy surfaces and determining the reaction coordinates. It is found to be quite different from that in liquid water. As shown by many authors, proton transfer in liquid water is promoted by the structure fluctuation, creating three-coordinated water molecules in the hydrogen bond network rearrangement, and the excess proton makes transitions among these three-coordinated water molecules as forming a so-called Zundel structure, (H5O2)+. This kind of large structural rearrangement cannot take place in ice. Nevertheless, the proton transfer in ice can be very fast. It is found that the strong constraint on the molecular geometry in ice is the source of the facile proton transfer. This constraint reduces the stabilization of the excess proton state in two ways: (1) as O–O cannot shrink freely, it cannot form a stable Zundel structure in which two water molecules share the excess proton locating at the center of ...

Dynamics of proton attachment to water cluster: Proton transfer, evaporation, and relaxation

A proton attachment dynamics to a water cluster is investigated by using a classical molecular dynamics calculation. It is found that three dynamical stages are involved: (1) ultrafast (∼10−14 s) proton attachment to a water molecule of the cluster which followed by (2) the fast (∼10−13 s) sequential proton transfer over several water molecules on the cluster surface and then, (3) the gradual (∼10−11 s) proton penetration to the cluster core. In the first two stages, the large kinetic energy of the order of hundreds kcal/mol is released to the system, which results in the evaporation of a few water molecules from the cluster. The water molecules evaporating in these early stages have large vibrational and translational energies. The mechanism of the energy relaxation and the proton transfer in each process are investigated. The large amplitude vibrational motion promotes sequential concerted proton exchange transfers in the earlier stages (1) and (2). The precise configurational matching of the hydrogen b...

Relation between the conformational heterogeneity and reaction cycle of Ras: molecular simulation of Ras.

Ras functions as a molecular switch by cycling between the active GTP-bound state and the inactive GDP-bound state. It is known experimentally that there is another GTP-bound state called state 1. We investigate the conformational changes and fluctuations arising from the difference in the coordinations between the switch regions and ligands in the GTP- and GDP-bound states using a total of 830 ns of molecular-dynamics simulations. Our results suggest that the large fluctuations among multiple conformations of switch I in state 1 owing to the absence of coordination between Thr-35 and Mg(2+) inhibit the binding of Ras to effectors. Furthermore, we elucidate the conformational heterogeneity in Ras by using principal component analysis, and propose a two-step reaction path from the GDP-bound state to the active GTP-bound state via state 1. This study suggests that state 1 plays an important role in signal transduction as an intermediate state of the nucleotide exchange process, although state 1 itself is an inactive state for signal transduction.

Mechanism of proton transfer in ice. II. Hydration, modes, and transport

The mechanism of the excess-proton transfer in ice is investigated by analyzing the potential energy surface, the normal modes, and the interaction between the excess proton and defects. It is found that the solvation from water molecules in long-distance shells is essential for the smooth transport of the proton. The solvation shells up to, for example, about the 18th shell are needed to attain a convergence of the excess-proton solvation energies. The potential energy surface of the excess-proton transfer calculated with including these distant hydration shells is very smooth even for a long distance proton transport. Normal modes are calculated along the reaction paths of the proton transfer. An analysis is done to find how the character of these normal modes changes along the proton transfer. The structure and energetics of hydronium ion and L-defect complex are also examined to explain the temperature dependence of the proton transport.

Dimensionality of Collective Variables for Describing Conformational Changes of a Multi-Domain Protein.

Collective variables (CVs) are often used in molecular dynamics simulations based on enhanced sampling algorithms to investigate large conformational changes of a protein. The choice of CVs in these simulations is essential because it affects simulation results and impacts the free-energy profile, the minimum free-energy pathway (MFEP), and the transition-state structure. Here we examine how many CVs are required to capture the correct transition-state structure during the open-to-close motion of adenylate kinase using a coarse-grained model in the mean forces string method to search the MFEP. Various numbers of large amplitude principal components are tested as CVs in the simulations. The incorporation of local coordinates into CVs, which is possible in higher dimensional CV spaces, is important for capturing a reliable MFEP. The Bayesian measure proposed by Best and Hummer is sensitive to the choice of CVs, showing sharp peaks when the transition-state structure is captured. We thus evaluate the required number of CVs needed in enhanced sampling simulations for describing protein conformational changes.

GENESIS 1.1: A hybrid-parallel molecular dynamics simulator with enhanced sampling algorithms on multiple computational platforms

GENeralized‐Ensemble SImulation System (GENESIS) is a software package for molecular dynamics (MD) simulation of biological systems. It is designed to extend limitations in system size and accessible time scale by adopting highly parallelized schemes and enhanced conformational sampling algorithms. In this new version, GENESIS 1.1, new functions and advanced algorithms have been added. The all‐atom and coarse‐grained potential energy functions used in AMBER and GROMACS packages now become available in addition to CHARMM energy functions. The performance of MD simulations has been greatly improved by further optimization, multiple time‐step integration, and hybrid (CPU + GPU) computing. The string method and replica‐exchange umbrella sampling with flexible collective variable choice are used for finding the minimum free‐energy pathway and obtaining free‐energy profiles for conformational changes of a macromolecule. These new features increase the usefulness and power of GENESIS for modeling and simulation in biological research.

Parallel implementation of 3D FFT with volumetric decomposition schemes for efficient molecular dynamics simulations

Three-dimensional Fast Fourier Transform (3D FFT) plays an important role in a wide variety of computer simulations and data analyses, including molecular dynamics (MD) simulations. In this study, we develop hybrid (MPI+OpenMP) parallelization schemes of 3D FFT based on two new volumetric decompositions, mainly for the particle mesh Ewald (PME) calculation in MD simulations. In one scheme, (1d_Alltoall), five all-to-all communications in one dimension are carried out, and in the other, (2d_Alltoall), one two-dimensional all-to-all communication is combined with two all-to-all communications in one dimension. 2d_Alltoall is similar to the conventional volumetric decomposition scheme. We performed benchmark tests of 3D FFT for the systems with different grid sizes using a large number of processors on the K computer in RIKEN AICS. The two schemes show comparable performances, and are better than existing 3D FFTs. The performances of 1d_Alltoall and 2d_Alltoall depend on the supercomputer network system and number of processors in each dimension. There is enough leeway for users to optimize performance for their conditions. In the PME method, short-range real-space interactions as well as long-range reciprocal-space interactions are calculated. Our volumetric decomposition schemes are particularly useful when used in conjunction with the recently developed midpoint cell method for short-range interactions, due to the same decompositions of real and reciprocal spaces. The 1d_Alltoall scheme of 3D FFT takes 4.7 ms to simulate one MD cycle for a virus system containing more than 1 million atoms using 32,768 cores on the K computer.

CHARMM Force-Fields with Modified Polyphosphate Parameters Allow Stable Simulation of the ATP-Bound Structure of Ca(2+)-ATPase.

Adenosine triphosphate (ATP) is an indispensable energy source in cells. In a wide variety of biological phenomena like glycolysis, muscle contraction/relaxation, and active ion transport, chemical energy released from ATP hydrolysis is converted to mechanical forces to bring about large-scale conformational changes in proteins. Investigation of structure-function relationships in these proteins by molecular dynamics (MD) simulations requires modeling of ATP in solution and ATP bound to proteins with accurate force-field parameters. In this study, we derived new force-field parameters for the triphosphate moiety of ATP based on the high-precision quantum calculations of methyl triphosphate. We tested our new parameters on membrane-embedded sarcoplasmic reticulum Ca(2+)-ATPase and four soluble proteins. The ATP-bound structure of Ca(2+)-ATPase remains stable during MD simulations, contrary to the outcome in shorter simulations using original parameters. Similar results were obtained with the four ATP-bound soluble proteins. The new force-field parameters were also tested by investigating the range of conformations sampled during replica-exchange MD simulations of ATP in explicit water. Modified parameters allowed a much wider range of conformational sampling compared with the bias toward extended forms with original parameters. A diverse range of structures agrees with the broad distribution of ATP conformations in proteins deposited in the Protein Data Bank. These simulations suggest that the modified parameters will be useful in studies of ATP in solution and of the many ATP-utilizing proteins.

Kinetic energy definition in velocity Verlet integration for accurate pressure evaluation

In molecular dynamics (MD) simulations, a proper definition of kinetic energy is essential for controlling pressure as well as temperature in the isothermal-isobaric condition. The virial theorem provides an equation that connects the average kinetic energy with the product of particle coordinate and force. In this paper, we show that the theorem is satisfied in MD simulations with a larger time step and holonomic constraints of bonds, only when a proper definition of kinetic energy is used. We provide a novel definition of kinetic energy, which is calculated from velocities at the half-time steps (t - Δt/2 and t + Δt/2) in the velocity Verlet integration method. MD simulations of a 1,2-dispalmitoyl-sn-phosphatidylcholine (DPPC) lipid bilayer and a water box using the kinetic energy definition could reproduce the physical properties in the isothermal-isobaric condition properly. We also develop a multiple time step (MTS) integration scheme with the kinetic energy definition. MD simulations with the MTS integration for the DPPC and water box systems provided the same quantities as the velocity Verlet integration method, even when the thermostat and barostat are updated less frequently.