Reaching new levels of realism in modeling biological macromolecules in cellular environments

Abstract

An increasing number of studies are aimed at modeling cellular environments in a comprehensive and realistic fashion. A major challenge in these efforts is how to bridge spatial and temporal scales over many orders of magnitude. Furthermore, there are additional challenges in integrating different aspects ranging from questions about biomolecular stability in crowded environments to the description of reactive processes on cellular scales. In this review, recent studies with models of biomolecules in cellular environments at different levels of detail are discussed in terms of their strengths and weaknesses. In particular, atomistic models, implicit representations of cellular environments, coarse-grained and spheroidal models of biomolecules, as well as the inclusion of reactive processes via reaction-diffusion models are described. Furthermore, strategies for integrating the different models into a comprehensive description of cellular environments are discussed.

Keywords: Brownian dynamics; Coarse-graining; Confinement; Crowding; Implicit solvent; Reaction–diffusion.

Figure 1

Fully atomistic model of biomolecules in a crowded environment.

Figure 2

Schematic model of diffusion of chymotrypsin inhibitor 2 (in yellow) in the presence of bovine serum albumin (left) and lysozyme (right).

Figure 3

Diffusion of villin (red) and protein G (green; blue) as a function of protein crowder volume fraction from simulations with error bars to indicating statistical errors from simulations of villin/protein G mixtures (red; green) or only protein G (blue).

Figure 4

Explicit solvent model of cellular environments (left) compared with intermediate dielectric model of water in crowded environments (center) and low dielectric model of cellular environments (right).

Figure 5

Coarse-grained, Cα-based model of a biomolecule in the presence of spherical crowders.

Figure 6

Spherical model of a biomolecule with embedded charges for basic (blue) and acidic (red) amino acids.

Figure 7

Detailed cytoplasmic model of Mycoplasma genitalium. Proteins and nucleic acids are shown with each complex in a different color.