In-Cell Dynamics: The Next Focus of All-Atom Simulations

Abstract

The cell is a crowded space where large biomolecules and metabolites are in continuous motion. Great strides have been made in in vitro studies of protein dynamics, folding, and protein−protein interactions, and much new data are emerging of how they differ in the cell. In this Perspective, we highlight the current progress in atomistic modeling of in-cell environments, both bacteria and mammals, with emphasis on classical all-atom molecular dynamics simulations. These simulations have been recently used to capture and characterize functional and non-functional protein−protein interactions, protein folding dynamics of small proteins with varied topologies, and dynamics of metabolites. We further discuss the challenges and efforts for updating modern force fields critical to the progress of cellular environment simulations. We also briefly summarize developments in relevant state-of-the-art experimental techniques. As computational and experimental methodologies continue to progress and produce more directly comparable data, we are poised to capture the complex atomistic picture of the cell.

Metastable States in the Hinge-Bending Landscape of an Enzyme in an Atomistic Cytoplasm Simulation

“…Here, we resolve hinge-bending transitions into and out of three states on the sub-microsecond to microsecond time scale at the atomic level using molecular dynamics (MD) simulations of hPGK in a human cytoplasm model and observe substrate binding on a similar time scale. We initially placed apo-hPGK (UnitProt ID P00558 residues M0–I416, PDB ID 2XE6 ) within two separate specially constructed atomistic models − (CellA and CellB; Figure A). The overall composition of CellA is ∼280 mg/mL macromolecules, ∼175 mM metabolites, and ∼190 mM inorganic ions.…”