Molecular dynamics simulations of large macromolecular complexes

Abstract

Connecting dynamics to structural data from diverse experimental sources, molecular dynamics simulations permit the exploration of biological phenomena in unparalleled detail. Advances in simulations are moving the atomic resolution descriptions of biological systems into the million-to-billion atom regime, in which numerous cell functions reside. In this opinion, we review the progress, driven by large-scale molecular dynamics simulations, in the study of viruses, ribosomes, bioenergetic systems, and other diverse applications. These examples highlight the utility of molecular dynamics simulations in the critical task of relating atomic detail to the function of supramolecular complexes, a task that cannot be achieved by smaller-scale simulations or existing experimental approaches alone.

Figure 1

Characteristic length-scales currently associated with varying levels of description in biomolecular simulations. Ab-initio and semi-empirical quantum mechanical calculations permit the study of chemical reactions in electronic detail within single molecules and small proteins while all-atom and coarsed-grained molecular dynamics simulations allow for the study of biological phenomena from the individual protein level to large subcellular organelles, and at all levels in between.

Figure 2

Viral particles of different sizes studied using MD simulations. The viruses were arranged in the order of increasing size with the capsid diameters given in parentheses : STMV (17 nm) [20], poliovirus (32 nm) [22], RHDV (43 nm) [15], SV40 (49 nm) [23], and HIV-1 (70–100 nm) [1]. For size comparison, HIV-1 protease, one of the most studied enzymes, is shown at the bottom right.

Figure 3

A. Translocating ribosome at the pre-translocation state with an A-site tRNA (red) and a P-site tRNA (green) [49]. A red arrow shows the direction of tRNA’s traversal motion. B. Insertion of a nascent protein by the ribosome into a nanodisc [50] membrane working with the SecYE translocon [51]. The nascent protein and P-site tRNA are shown in green. A red arrow shows the direction of the nascent protein’s insertion motion. C. Bacterial ribosome with the antibiotic drug erythromycin (in red circle) shown at its binding site inside the ribosome [16].

Figure 4

Photosynthetic membrane studied by molecular dynamics simulations. MD simulations provide insight into local and global mechanisms of light harvesting and energy conversion. The photosynthetic membrane pictured consists of three types of protein complexes, light harvesting complex 1 (light blue) and 2 (green) and photosynthetic reaction center (dark blue) as well as quinone molecules (red), which are surrounded by a phospholipid membrane (translucent gray). The full system simulated contains ~23 million million atoms [71]*.

Figure 5

Membrane sculpting by F-BAR domains. Shape-based coarse-grained model simulations identified optimal lattice structures that maximize membrane curvature [87]*. Membrane lipids are shown in green and individual F-BAR domain within the lattice by the remaining colors seen.