Molecular Dynamics Simulation for All

Abstract

The impact of molecular dynamics (MD) simulations in molecular biology and drug discovery has expanded dramatically in recent years. These simulations capture the behavior of proteins and other biomolecules in full atomic detail and at very fine temporal resolution. Major improvements in simulation speed, accuracy, and accessibility, together with the proliferation of experimental structural data, have increased the appeal of biomolecular simulation to experimentalists-a trend particularly noticeable in, although certainly not limited to, neuroscience. Simulations have proven valuable in deciphering functional mechanisms of proteins and other biomolecules, in uncovering the structural basis for disease, and in the design and optimization of small molecules, peptides, and proteins. Here we describe, in practical terms, the types of information MD simulations can provide and the ways in which they typically motivate further experimental work.

Keywords: MD simulations; allostery; biomolecular simulation; conformational change; drug design; drug discovery; experimental design; protein; structural biology.

Figure 1.. Growth of molecular dynamics simulations in structural biology.

For the top 250 journals by impact factor, we plot the number of publications per year that include the term “molecular dynamics” in either the title, abstract or keywords. Analysis was performed via Web of Science (https://webofknowledge.com/) in February 2018.

Figure 2.. Applications of molecular dynamics simulations.

Here we illustrate some of the most common applications of MD simulations.

Figure 3.. Case study: structural basis of allosteric modulation in GPCRs.

We used MD simulations to determine how allosteric modulators bind to a GPCR, the M2 muscarinic acetylcholine receptor, and how these allosteric modulators increase or decrease binding affinity of orthosteric ligands. A) The conformations of the orthosteric and allosteric binding sites in the presence or absence of different ligands, as determined by MD simulations. The orthosteric ligand N-Methyl Scopolamine (NMS) favors an enlarged allosteric site. Binding of the positive allosteric modulator (PAM) alcuronium requires a larger allosteric site to bind, whereas the negative allosteric modulator (NAM) C₇/3-phth does not. B) To validate the proposed mechanism of allostery, we designed a modified version of the NAM that would require a larger allosteric pocket to bind, and is thus predicted to have less negative cooperativity. Indeed, radioligand binding experiments revealed that the cooperativity of the designed modulator is fourfold less negative than that of the original NAM, even though the affinity of the designed modulator is higher. Adapted from (Dror et al., 2013), with permission.

Figure 4.. Case study: atomic-level mechanism of an alternating access transporter.

A) MD simulations captured the spontaneous transition of the sugar transporter SemiSWEET from its outward-open state (where the substrate-binding pocket is accessible to the outside of the cell) to its inward-open state, along with the accompanying substrate translocation process. This simulation study addressed several long-standing questions such as what drives the structural changes associated with transport, how the presence of the substrate affects the conformations the transporter adopts, and how the inner and outer gates avoid opening simultaneously. B) Overlays of simulation snapshots and the corresponding crystal structures of the occluded and inward facing states show that conformations visited in simulation are nearly identical to those observed crystallographically. Mutagenesis studies further validated simulation results. Adapted from (Latorraca et al., 2017), with permission. Hollingsworth and Dror review modern molecular dynamics (MD) simulations, with an emphasis on how such simulations complement wet-lab experiments. MD simulations capture biomolecular motion in atomic detail and have come into widespread use thanks to recent technological and scientific advances.

Figure 5.. Case study: how GPCRs cause arrestin activation.

A) A crystal structure of GPCR-bound, active-state arrestin. The receptor’s core and phosphorylated tail (R_P tail) bind to distinct surfaces of arrestin, and their respective influences on arrestin conformation have been unclear. Upon activation, the C-domain of arrestin twists 18º relative to the N-domain. C) Distributions of the interdomain twist angles under different simulation conditions are shown. Simulations indicate that binding of either the receptor core or the R_P tail is sufficient to activate arrestin, with binding of both the core and R_P tail leading to an even larger activation effect. D, E) Site-directed fluorescence spectroscopy experiments support these computational results. These experiments probe conformational change in arrest in at either the core interface or the R_P tail interface (E) and show that receptor constructs that bind only at the core interface or only at the R_P tail cause conformational changes at both interfaces. Adapted from (Latorraca et al., 2018), with permission.