Simulations of biomolecular functions by a simultaneous use of three levels
of molecular simulations, QM, MM, and CG
Prof. Akinori Kidera
Molecular Scale Team, Integrated Simulation of Living Matter Group,
Computational Science Research Program, RIKEN
The goal of the Molecular Scale Team is to understand the biological functions at the level of biomolecules as is possible by virtually activating the molecules in the supercomputer with fully utilizing the molecular simulation methods. Biomolecular functions at the single molecular level can be stated rigorously in physical terms as “A series of protein structure changes as a response to an external perturbation such as ligand binding, and accompanying chemical reactions” A protein function starts with an external perturbation imposed on the protein system. The response to the perturbation initiates the relaxation process to a new equilibrium structure, resulting in a structural change in the protein. The structural change accompanies a chemical reaction in the ligand molecule, converting it into a product. The product molecule and/or the protein in the new equilibrium structure in turn become the perturbation for another protein system. This process can occur in multiple stages, and we thus used the term “a series” at the top of the definition of functional motions of proteins. In order to simulate such biomolecular functions, we thus have to make use of the two methods of molecular simulation, quantum chemistry calculation (QM) handling first principle calculations of chemical reactions and all-atom molecular dynamics simulation (MM) solving the Newtonian equations of motion to calculate the biomolecular movements. In addition, to avoid an intractable increase in the computational burden, despite the power of the supercomputer, in treating larger size biomolecular systems involving longer time-scale motions, we need the third technique, coarse grained model calculation (CG). This method is crucially important also in considering the cellular environment for the simulation systems. Consequently, we try to express simulation systems of biomolecules in the three levels of QM, MM and CG. In the presentation, we will introduce our efforts to establish the three levels of molecular simulation techniques as well as recent results of molecular simulations using these methods, focusing on the target system of the team, multi-drug efflux transporter AcrB. In addition, we are trying to develop methods for coupling different levels of simulation techniques, i.e., QM/MM and MM/CG, in order to accelerate the simulation speed with maintaining the accuracy. Using all of these techniques, we are tackling the problems of biomolecular functions.