A Systematic Methodology for Defining Coarse-Grained Sites in Large Biomolecules

Abstract

Coarse-grained (CG) models of biomolecules have recently attracted considerable interest because they enable the simulation of complex biological systems on length-scales and timescales that are inaccessible for atomistic molecular dynamics simulation. A CG model is defined by a map that transforms an atomically detailed configuration into a CG configuration. For CG models of relatively small biomolecules or in cases that the CG and all-atom models have similar resolution, the construction of this map is relatively straightforward and can be guided by chemical intuition. However, it is more challenging to construct a CG map when large and complex domains of biomolecules have to be represented by relatively few CG sites. This work introduces a new and systematic methodology called essential dynamics coarse-graining (ED-CG). This approach constructs a CG map of the primary sequence at a chosen resolution for an arbitrarily complex biomolecule. In particular, the resulting ED-CG method variationally determines the CG sites that reflect the essential dynamics characterized by principal component analysis of an atomistic molecular dynamics trajectory. Numerical calculations illustrate this approach for the HIV-1 CA protein dimer and ATP-bound G-actin. Importantly, since the CG sites are constructed from the primary sequence of the biomolecule, the resulting ED-CG model may be better suited to appropriately explore protein conformational space than those from other CG methods at the same degree of resolution.

Nucleotide-dependent conformational states of actin

“…These results reveal correlation between the dynamics of the DB loop region and the state of the bound nucleotide. This correlation is also consistent with a previous coarse-grained study that found the dynamics of the DB loop region in ATP monomeric actin to be distinct from the rest of the protein (40).…”

Order parameters for macromolecules: Application to multiscale simulation

“…Earlier choices for OP-like variables include principal component analysis (PCA) modes to identify collective behaviors in macromolecular systems, [13][14][15] dihedral angles, 16,17 curvilinear coordinates to characterize macromolecular folding and coiling, 18 bead models wherein a peptide or nucleotide is represented by a bead which interacts with others via a phenomenological force, and spatial coarse-grained models. [19][20][21] These approaches suffer from one or more of the following difficulties: (1) characteristic variables are not slowly varying in time; (2) macromolecular twist is not readily accounted for; (3) their internal dynamics, and hence inelasticity of their collisions is neglected; and (4) the forces involved must be calibrated for most new applications. In contrast as discussed in Secs.…”

“…For big systems, this becomes computationally expensive. 21 Improvements to EDS have been made via a technique called amplified collective motion. However normal modes derived from this model via an anisotropic network 13 may not be consistent with all-atom models, especially if the structure undergoes severe deformation.…”

Coarse Point Charge Models For Proteins From Smoothed Molecular Electrostatic Potentials

“…The authors show that, in protein association, their model provides a good approximation of the all-atom potential, if the distance between the protein surfaces is larger than the diameter of a solvent molecule. In a recent work, Zhang et al 8 proposed a method to define CGs that reflect the collective motions computed by a principal component analysis of an atomistic MD trajectory. Each CG site is the com of a domain, i.e., a group of contiguous CR atoms that move in a highly correlated fashion.…”