Molecular dynamics and protein function

Abstract

A fundamental appreciation for how biological macromolecules work requires knowledge of structure and dynamics. Molecular dynamics simulations provide powerful tools for the exploration of the conformational energy landscape accessible to these molecules, and the rapid increase in computational power coupled with improvements in methodology makes this an exciting time for the application of simulation to structural biology. In this Perspective we survey two areas, protein folding and enzymatic catalysis, in which simulations have contributed to a general understanding of mechanism. We also describe results for the F(1) ATPase molecular motor and the Src family of signaling proteins as examples of applications of simulations to specific biological systems.

Fig. 1.

Simulation of a solvated protein. This slice through a simulation system shows a Src kinase protein (green) surrounded by ≈15,000 water molecules (oxygen atoms are red and hydrogen atoms are white). The simulation system consists of ≈50,000 atoms, including potassium and chloride ions (purple and orange spheres, respectively). A 1-ns molecular dynamics trajectory for this system can be generated in 4 days by using a cluster of four inexpensive Linux-based computers. (Courtesy of Olga Kuchment.)

Fig. 2.

Simulations of the folding of a three-helix bundle protein. (a and b)(Upper) Semilog plots of the time dependence of the fractions of native helical and interhelical contacts and the inverse fractions of native volume (calculated from the inverse cube of the radius of gyration) for two different trajectories. (Lower) Structures of the protein molecule at selected times. [Reproduced with permission from ref. (Copyright 1999, Nature Publishing Group).]

Fig. 3.

Mechanism of TIM. (a) Electrostatic contribution of individual residues (in kcal/mol on the ordinate) to the lowering of the activation energy barrier (TS1) of the reaction of the DHAP substrate to form the enolate intermediate. This is the rate-determining step of the overall chemical reaction. The residues are plotted on the abscissa as a function of the distance from the C_α carbon of the residue [or the oxygen of a water molecule (W)] to C₁ of the substrate. Negative values correspond to the lowering of the barrier. (b) Active-site structure at transition state showing important residues and water molecules. [Reproduced with permission from ref. (Copyright 2004, AAAS).]

Fig. 4.

F₁ ATPase and targeted molecular dynamics. (a) Structure of F_o–F₁ ATP synthase based on crystal structures of the F₁ ATPase (51, 52). The F_o component is indicated as a gray cylinder within the membrane (yellow), and the γ-subunit shaft is shown in green. The three α-subunits are indicated by blue backbone traces, and the molecular surfaces of the three β-subunits are shown. The γ-subunit rotates in a clockwise direction during ATP synthesis, as viewed from the membrane, and the effects of a 120° rotation of the γ-subunit are manifested as a change in the conformation of the β-subunits. (b) Schematic representation of targeted molecular dynamics. The simulated structure is restrained to be at a specified rms distance from the target structure, and this distance is gradually decreased during the simulation. Because the restraint is applied in an overall rms sense, the intermediate structures are not specified explicitly and different parts of the structure can relax toward the final structures at different rates.

Fig. 5.

Structure and dynamics of the Src and Abl kinases. (Left) The structures of c-Abl (green) and c-Src (red) are shown superimposed on their SH2 and SH3 domains (69, 70, 75). Note the dissimilarity in the conformation of the kinase domains. (Center and Right) The results of unbiased molecular dynamics simulations of c-Src. Residues in different domains that move in a correlated manner in the simulation are linked by a red line. These correlations were calculated by superimposing each instantaneous structure in the simulation on the C-terminal lobe of the kinase domain, and motions that are correlated to the C-terminal lobe are removed by this procedure. (Right) The mutation of residues in the SH2–SH3 linker to glycine reduces the correlation in the dynamics of these domains. Similar results were obtained for c-Abl. (Modified from refs. and 75).