Steered molecular dynamics: a tool to investigate molecular interactions

Steered molecular dynamics (SMD) induces unbinding of ligands and conformational changes in biomolecules on time scales accessible to molecular dynamics simulations. Time-dependent external forces are applied to a system, and the response of the system is analyzed. In this work, the application of the technique to several biomolecular systems is described. (1) SMD simulations were employed to induce, over periods of 40 to 600 ps, the unbinding of biotin from avidin by means of external harmonic forces with a variety of loading rates. The applied forces reduced the overall binding energy sufficiently to yield unbinding within the measurement time. The simulations revealed a variety of unbinding pathways, the contribution of amino acid residues and water molecules to adhesion, as well as the spatial range over which avidin binds biotin. No particular scaling of the maximum applied force with the loading rate was observed. (2) Movement of one of the domains of the mitochondrial cytochrome bc1 complex controls the bifurcation of the electron transfer governing the energy transduction in the complex. A solvated structure of the complex in a phospholipid bilayer was modeled. The domain movement was induced in SMD simulations by applying a torque to the mobile part of the protein. The contacts made by the mobile domain with the rest of the protein during the rotation provided insights into the overall mechanism of the domain movement. (3) The wealth of information that can be gained from SMD simulations was further demonstrated in the studies of the binding of retinal to bacterio-opsin, the extraction of a lipid molecule from a monolayer of dilauroyl-phosphatidyl-ethanolamin lipids into the active site of human synovial phospholipase A2 and into the aqueous phase, and the binding and unbinding of all-trans retinoic acid to/from human retinoic acid receptor (hRAR)-ϒ. The non-equilibrium statistical mechanics theory underlying the analysis of SMD results is developed. One-dimensional stochastic models were formulated in terms of Langevin and the associated Smoluchowski equations, together with the theory of first passage times. These models demonstrate that picosecond to nanosecond simulations of ligand unbinding result in protein-ligand motion far from the thermally activated regime of millisecond atomic force microscopy experiments. It is also demonstrated that time series data from molecular dynamics simulations of ligand unbinding can be used to reconstruct the essential features of the binding potential of macromolecules within the limits set by the fluctuation-dissipation theorem.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Physics

Year dc:date

2012

Author dc:creator

• Izrailev, Sergei Felixovich

Contributors dc:contributor

• Schulten, Klaus J.

• steered molecular dynamics

Statement dc:rights

• ©1999 Sergei Felixovich Izrailev

Language dc:language

en

Identifier

4191926

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/30881