Efficacy of independence sampling in replica exchange simulations of ordered and disordered proteins

Recasting temperature replica exchange (T‐RE) as a special case of Gibbs sampling has led to a simple and efficient scheme for enhanced mixing (Chodera and Shirts, J. Chem. Phys., 2011, 135, 194110). To critically examine if T‐RE with independence sampling (T‐REis) improves conformational sampling, we performed T‐RE and T‐REis simulations of ordered and disordered proteins using coarse‐grained and atomistic models. The results demonstrate that T‐REis effectively increase the replica mobility in temperatures space with minimal computational overhead, especially for folded proteins. However, enhanced mixing does not translate well into improved conformational sampling. The convergences of thermodynamic properties interested are similar, with slight improvements for T‐REis of ordered systems. The study re‐affirms the efficiency of T‐RE does not appear to be limited by temperature diffusion, but by the inherent rates of spontaneous large‐scale conformational re‐arrangements. Due to its simplicity and efficacy of enhanced mixing, T‐REis is expected to be more effective when incorporated with various Hamiltonian‐RE protocols. © 2017 Wiley Periodicals, Inc.     

Ab initio prediction of protein-ligand binding structures by replica-exchange umbrella sampling simulations

We have developed a prediction method for the binding structures of ligands with proteins. Our method consists of three steps. First, replica-exchange umbrella sampling simulations are performed along the distance between a putative binding site of a protein and a ligand as the reaction coordinate. Second, we obtain the potential of mean force (PMF) of the unbiased system using the weighted histogram analysis method and determine the distance that corresponds to the global minimum of PMF. Third, structures that have this global-minimum distance and energy values around the average potential energy are collected and analyzed using the principal component analysis. We predict the binding structure as the global-minimum free energy state on the free energy landscapes along the two major principal component axes. As test cases, we applied our method to five protein-ligand complex systems. Starting from the configuration in which the protein and the ligand are far away from each other in each system, our method predicted the ligand binding structures in excellent agreement with the experimental data from Protein Data Bank.     

Does Hamiltonian Replica Exchange via Lambda-Hopping Enhance the Sampling in Alchemical Free Energy Calculations?

In the context of computational drug design, we examine the effectiveness of the enhanced sampling techniques in state-of-the-art free energy calculations based on alchemical molecular dynamics simulations. In a paradigmatic molecule with competition between conformationally restrained E and Z isomers whose probability ratio is strongly affected by the coupling with the environment, we compare the so-called λ-hopping technique to the Hamiltonian replica exchange methods assessing their convergence behavior as a function of the enhanced sampling protocols (number of replicas, scaling factors, simulation times). We found that the pure λ-hopping, commonly used in solvation and binding free energy calculations via alchemical free energy perturbation techniques, is ineffective in enhancing the sampling of the isomeric states, exhibiting a pathological dependence on the initial conditions. Correct sampling can be restored in λ-hopping simulation by the addition of a “hot-zone” scaling factor to the λ-stratification (FEP⁺ approach), provided that the additive hot-zone scaling factors are tuned and optimized using preliminary ordinary replica-exchange simulation of the end-states.     

The Stochastic Traveling Salesman Problem: Finite Size Scaling and the Cavity Prediction

We study the random link traveling salesman problem, where lengths l _ij between city i and city j are taken to be independent, identically distributed random variables. We discuss a theoretical approach, the cavity method, that has been proposed for finding the optimum tour length over this random ensemble, given the assumption of replica symmetry. Using finite size scaling and a renormalized model, we test the cavity predictions against the results of simulations, and find excellent agreement over a range of distributions. We thus provide numerical evidence that the replica symmetric solution to this problem is the correct one. Finally, we note a surprising result concerning the distribution of k th-nearest neighbor links in optimal tours, and invite a theoretical understanding of this phenomenon.     

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. © 2017 Wiley Periodicals, Inc.     

Electrical and Optical Properties of Conducting Polymer and Carbons in Nano-Scale Periodic Structure and their Intercalation Effects

Abstract

Nano-scale periodic structures of conducting polymer and carbons, which were prepared by infiltration of polymers and carbons in nano-scale interconnected periodic pores in synthetic opals made of regular array of SiO₂ spheres and then removing SiO₂ by etching, have been found to exhibit novel electrical and optical properties. Their electrical and optical properties in thus fabricated conducting polymer and carbon replicas change drastically upon pyrolysis due to progress of carbonization and graphitization. That is, due to the changes in periodicity, pore size, carbonization degree and crystal structure, electrical conductivity, magnetoconductance and their temperature dependences and optical reflection spectra have changed drastically. These replicas with porous nature can be infiltrated and also intercalated with various materials, resulting in also remarkable changes of properties. The synthetic opal infiltrated with conducting polymer can be electrochemically doped, with which remarkable change of optical properties have been observed due to the shift of the diffraction peak accompanying with the change in refractive index. Alkali metal intercalated carbon and graphite with nano-scale periodic structures have been also studied. The applications of these nano-scale periodic structures of conducting polymer and carbon are also discussed.     

Water in the presence of inert Lennard-Jones obstacles

Water confined by the presence of a ‘sea’ of inert obstacles was examined. In the article, freely mobile two-dimensional Mercedes-Benz (MB) water put to a disordered, but fixed, matrix of Lennard-Jones disks was studied by the Monte Carlo computer simulations. For the MB water molecules in the matrix of Lennard-Jones disks, we explored the structures, hydrogen-bond-network formation and thermodynamics as a function of temperature and size and density of matrix particles. We found that the structure of model water is perturbed by the presence of the obstacles. Density of confined water, which was in equilibrium with the bulk water, was smaller than the density of the bulk water and the temperature dependence of the density of absorbed water did not show the density anomaly in the studied temperature range. The behaviour observed as a consequence of confinement is similar to that of increasing temperature, which can for a matrix lead to a process similar to capillary evaporation. At the same occupancy of space, smaller matrix molecules cause higher destruction effect on the absorbed water molecules than the bigger ones. We have also tested the hypothesis that at low matrix densities the obstacles induce an increased ordering and ‘hydrogen bonding’ of the MB model molecules, relative to pure fluid, while at high densities the obstacles reduce MB water structuring, as they prevent the fluid to form good ‘hydrogen-bonding’ networks. However, for the size of matrix molecules similar to that of water, we did not observe this effect.