Advances in coarse-grained modeling of macromolecular complexes

Abstract

Recent progress in coarse-grained (CG) molecular modeling and simulation has facilitated an influx of computational studies on biological macromolecules and their complexes. Given the large separation of length-scales and time-scales that dictate macromolecular biophysics, CG modeling and simulation are well-suited to bridge the microscopic and mesoscopic or macroscopic details observed from all-atom molecular simulations and experiments, respectively. In this review, we first summarize recent innovations in the development of CG models, which broadly include structure-based, knowledge-based, and dynamics-based approaches. We then discuss recent applications of different classes of CG models to explore various macromolecular complexes. Finally, we conclude with an outlook for the future in this ever-growing field of biomolecular modeling.

Figure 1.

Different avenues of approach for model development of highly coarse-grained (CG) macromolecules, which are broadly classified into structure-based, knowledge-based, and dynamics-based strategies. Here, the capsid and spacer peptide 1 (CA-SP1) domains of the human immunodeficiency virus (HIV) protein is used as a representative example. (Top) Each model class relies on different training datasets and methods; for example, an experimental structure (PDB 5L93), an extended dataset of experimental measurements (PDB 5L93, 3ZX8, 3J37 and 6BVF), or statistics from an all-atom molecular dynamics trajectory (initial structures from PDB 5L93), respectively. (Bottom) Resultant models can be classified as network-based and native-contact-based models (or hybrids thereof); bonded (nonbonded) interactions are depicted by solid purple (cyan) lines while CG sites (per residue) are depicted as spheres.

Figure 2.

Two representative applications of coarse-grained modeling. (A) Schematic of the closed loop complex of RNA polymerase (colored surface) and RNA (yellow balls) [left] with large-scale collective motions indicated by the teal arrows along the bridge helix [right] (adapted from Ref. [34]). (B) Self-assembly pathway of the human immunodeficiency virus (HIV) CA capsid protein subunits in forming the mature capsid of infectious virions. Identified are CA hexamers (green), pentamers (red) and the growing edge of the conical capsid (blue) (adapted from Ref. [35]).