Spotting the difference in molecular dynamics simulations of biomolecules

Shun Sakuraba,Hidetoshi Kono

doi:10.1063/1.4961227

Abstract

Comparing two trajectories from molecular simulations conducted under different conditions is not a trivial task. In this study, we apply a method called Linear Discriminant Analysis with ITERative procedure (LDA-ITER) to compare two molecular simulation results by finding the appropriate projection vectors. Because LDA-ITER attempts to determine a projection such that the projections of the two trajectories do not overlap, the comparison does not suffer from a strong anisotropy, which is an issue in protein dynamics. LDA-ITER is applied to two test cases: the T4 lysozyme protein simulation with or without a point mutation and the allosteric protein PDZ2 domain of hPTP1E with or without a ligand. The projection determined by the method agrees with the experimental data and previous simulations. The proposed procedure, which complements existing methods, is a versatile analytical method that is specialized to find the "difference" between two trajectories.

Highlights

Molecular dynamics (MD) simulations provide atomistic details of biomolecular motions
We note that different pseudorandom number seeds for the Langevin dynamics were used among simulations — in our preliminary calculation, we found that the Langevin dynamics with the same pseudorandom number seeds led to a significant statistical bias; a similar bias problem has been reported in the literature
The LDA-ITER algorithm was first applied to the trajectories of (1) the wild-type and R96H mutant of T4 lysozyme (T4L) and (2) the holo and apo structures of PDZ2

Summary

Introduction

Molecular dynamics (MD) simulations provide atomistic details of biomolecular motions. Such simulations are often described as “computational microscopy” of the molecule because they provide an additional perspective relative to other experimental results. When analyzing the function of a protein or a nucleic acid molecule, typically two or more simulations with different system setups are performed in parallel. To determine the effect of a mutation on one residue, two simulations are performed under the same conditions except for the mutated residue, and their differences are investigated Such cases include changes in the ligand-binding state (apo/holo), changes in the ligand molecule, mutations on protein residues or nucleic acid bases, or differences in thermodynamic variables such as pressure. It is common to quantify the structural changes with a distance matrix, which is represented as a colored map with the abscissa and the ordinate both being the index (e.g., residue number) of the representative atoms (e.g., C-α atoms) and the color representing the a)Current address: Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba 277-8561, Japan

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