Abstract

Proteins, nucleic acids, and other biomacromolecules work as molecular machinery in a living cell. The effect of cellular environments on protein structure and function have been examined experimentally or theoretically. Since the inside of a cell is highly crowded with a large number of biomacromolecules, macromolecular crowding effect has been considered as one of the most important cellular effects on proteins. However, conventional methodologies and software hindered us from performing reliable molecular simulations in the environments. The GENESIS (GENeralized-Ensemble SImulation System) software has been developed to overcome the difficulty by introducing advanced techniques in parallelization and optimization of the code [1,2]. Using GENESIS , we succeeded in atomistic simulations of the bacterial cytoplasm [3] and an entire gene locus (GATA4) [4], which include more than 100 million and 1 billion atoms in their simulation systems, respectively. We also have extended the simulation time limitation by developing various enhanced conformational sampling methods [5] as well as allowing a large time step using a new definition of temperature in MD simulation [6]. Atomistic MD simulations of the bacterial cytoplasm have revealed the importance of weak non-specific interactions between proteins and between proteins and metabolites. This might be important for in-silico drug discovery in near future.

References [1] Jung et al. WIRE ’s Rev. Comp. Mol. Sci. 2015, 5, 310-323. [2] Kobayashi et al. JCC 2017 , 38, 2193-2206. [3] Yu et al. eLife 2016, 5, 1-22. [4] Jung et al. JCC 2019 , 40, 1919-1930. [5] For a review; Sugita et al. Biomolecular Simulations, 155-177, Springer, 2019. [6] Jung et al. JCTC 2019 , 15, 84-94.