Protein assembly and crowding simulations

Abstract

Proteins encounter frequent molecular interactions in biological environments. Computer simulations have become an increasingly important tool in providing mechanistic insights into how such interactions in vivo relate to their biological function. The review here focuses on simulations describing protein assembly and molecular crowding effects as two important aspects that are distinguished mainly by how specific and long-lived protein contacts are. On the topic of crowding, recent simulations have provided new insights into how crowding affects protein folding and stability, modulates enzyme activity, and affects diffusive properties. Recent studies of assembly processes focus on assembly pathways, especially for virus capsids, amyloid aggregation pathways, and the role of multivalent interactions leading to phase separation. Also, discussed are technical challenges in achieving increasingly realistic simulations of interactions in cellular environments.

Figure 1.. Crowding effects on ligand binding.

Distribution of small molecule inhibitor PP1 (red densities) and bovine serum albumin crowder (blue densities) around c-Src kinase (green) at dilute conditions and at different crowder concentrations (adapted from Fig. 1 in Kasahara et al. [16]; alternate PP1 ligand binding pathways to c-Src kinase in TYR-in and TYR-out conformations favored by crowding (adapted from Fig. 5 in Kasahara et al. [16]).

Figure 2.. Amyloid assembly pathways.

Schematic diagram of Aβ_16–22 fibril elongation mechanism with kinetic traps due to β-sheet misregistration (adapted from Fig. 6 in Proc. Natl. Acad. Sci. U.S.A. 2020, 117:10322; Copyright (2020) National Academy of Sciences).

Figure 3.. Molecular model of a bacterial periplasm.

Snapshot of a crowded double-membrane system with proteins (green) and antibiotic polymyxin (yellow) (Reprinted from Structure 2021, 29:444–456.e442 with permission from Elsevier).