Where soft matter meets living matter — protein structure, stability, and folding in the cell

A protein is a biopolymer that self-assembles through the process of protein folding. A cell is a crowded space where the surrounding macromolecules of a protein can limit the number of ways of folding. These crowding macromolecules can also affect the shape and the size of a physically malleable, or ‘soft, squishy’, protein with regulatory purposes. In this review, we focus on the in silico approaches of coarse-grained molecular simulations that enable the investigation of protein folding in a cell-like environment. When these simulation results were compared with experimentally measured properties of a protein, such joint effort has yielded new ideas on the specific function of a protein in cells. We also highlighted the recent developments of computer modeling and simulations that encompass the importance of the shape of a macromolecule, the interactions between macromolecules, and the hydrodynamic interactions on the kinetics and thermodynamics of a protein in a high concentration of protein solution and in cytoplasmic environments.

► Coarse-grained molecular simulations are used to investigate proteins under cell-like conditions. ► Macromolecular crowding effects can impact protein folding under cell-like conditions. ► Malleable proteins can sample several compact conformations driven by crowding effects. ► The structure-function of a protein inside a cell may not be shown in a test tube. ► Modeling of cytosolic solution can be the next challenge.