Abstract

We investigated the dissociation process of tri-N-acetyl-d-glucosamine from hen egg white lysozyme using parallel cascade selection molecular dynamics (PaCS-MD), which comprises cycles of multiple unbiased MD simulations using a selection of MD snapshots as the initial structures for the next cycle. Dissociation was significantly accelerated by PaCS-MD, in which the probability of rare event occurrence toward dissociation was enhanced by the selection and rerandomization of the initial velocities. Although this complex was stable during 1 μs of conventional MD, PaCS-MD easily induced dissociation within 100-101 ns. We found that velocity rerandomization enhances the dissociation of triNAG from the bound state, whereas diffusion plays a more important role in the unbound state. We calculated the dissociation free energy by analyzing all PaCS-MD trajectories using the Markov state model (MSM), compared the results to those obtained by combinations of PaCS-MD and umbrella sampling (US), steered MD (SMD) and US, and SMD and the Jarzynski equality, and experimentally determined binding free energy. PaCS-MD/MSM yielded results most comparable to the experimentally determined binding free energy, independent of simulation parameter variations, and also gave the lowest standard errors.

Highlights

  • Calculation of free energy differences between distinct molecular states has a long history and remains an active research theme in computational chemistry, physics, and biophysics

  • The negatively charged residues in the cleft are surrounded by the positively charged and hydrophobic residues. triNAG formed long-lasting hydrogen bonds with ASN59, TRP62, TRP63, ASP101, ASN103, and ALA107 of LYZ during the 1 μs conventional Molecular dynamics (MD) run, identical to those found in the crystal structure (PDB ID: 1HEW)[31] and by other computational studies.[32−34] Of the above-listed residues, ASP52 is known to play several key roles in catalysis.[66]

  • Using multicanonical MD, Kamiya et al showed that ASP101 and TRP62 are important amino acids for the interaction of triNAG and LYZ during the association process.[69]

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Summary

Introduction

Calculation of free energy differences between distinct molecular states has a long history and remains an active research theme in computational chemistry, physics, and biophysics. Computational methods for determining free energy can be categorized into four major groups: thermodynamic integration (TI), sampling-based methods, nonequilibrium dynamics, and adaptive biasing techniques.[1] Kirkwood[2] first introduced TI, which is widely used. Zwanzig proposed alchemical free energy perturbation, which decomposes a free energy change into multiple intermediate steps.[3]. The free energy perturbation approach was extended to methods based on reaction coordinates, including umbrella sampling (US).[4,5] Of the nonequilibrium dynamics methods, the Jarzynski equality[6] is the most widely used to determine the relation between free energy change and nonequilibrium trajectories. E.g., metadynamics[7,8] and Wang−Landau methods,[9] monitor the reaction coordinates and penalize the visited region by using adaptive forces.[1]

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