Multiscale methods for macromolecular simulations

Abstract

In this article we review the key modeling tools available for simulating biomolecular systems. We consider recent developments and representative applications of mixed quantum mechanics/molecular mechanics (QM/MM), elastic network models (ENMs), coarse-grained molecular dynamics, and grid-based tools for calculating interactions between essentially rigid protein assemblies. We consider how the different length scales can be coupled, both in a sequential fashion (e.g. a coarse-grained or grid model using parameterization from MD simulations), and via concurrent approaches, where the calculations are performed together and together control the progression of the simulation. We suggest how the concurrent coupling approach familiar in the context of QM/MM calculations can be generalized, and describe how this has been done in the CHARMM macromolecular simulation package.

Figure 1

Schematic representation of a CG-MD simulation of the self-assembly of a lipid bilayer/protein system from randomly positioned lipid (and water – not shown) molecules plus a know membrane protein structure. After ~ 0.25 μs of simulation the protein is stably inserted in a bilayer. The representation of the protein on the left illustrates the use of an elastic network model (in red) to restrain the structure of the protein.

Figure 2

A map object and its properties. A map object is defined as a grid with a given property mapped on the grid points. This could be either e.g. experimentally determined electron density or properties (e.g. electrostatic charges) generated from reference molecules.

Figure 3

Steps to derive molecular assembly structures by fitting molecular structures into electron microscopy maps. This is illustrated using a T-cell receptor (TCR) variable domain (PDB code: 1a7n) as an example complex to illustrate the modelling process with map objects. The TCR variable domain is a complex of two chains. The two chains are first blurred into maps of the same resolution (here 15 Å) as the EM map. Then each map is fitted into the EM map to get complex map. The complex map is projected back to atomic structures, which is the complex structure we are looking for. The root-mean-square (rms) deviations of the fitting result from X-ray complex is 3 Å.

Scheme 1