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Proc Natl Acad Sci U S A. 2004 Oct 26;101(43):15330-4. Epub 2004 Oct 15.

Unveiling functional protein motions with picosecond x-ray crystallography and molecular dynamics simulations.

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  • 1Laboratory of Chemical Physics, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-0520, USA. hummer@helix.nih.gov

Abstract

A joint analysis of all-atom molecular dynamics (MD) calculations and picosecond time-resolved x-ray structures was performed to gain single-molecule insights into mechanisms of protein function. Ensemble-averaged MD simulations of the L29F mutant of myoglobin after ligand dissociation reproduce the direction, amplitude, and time scales of crystallographically determined structural changes. This close agreement with experiments at comparable resolution in space and time validates the individual MD trajectories. From 1,700 single-molecule trajectories, we identified and structurally characterized a conformational switch that directs dissociated ligands to one of two nearby protein cavities. Subsequent ligand migration proceeds through a network of transiently interconnected internal cavities, with passage between them involving correlated protein-ligand motions. The simulations also suggest how picosecond protein motions modulate the functional dissociation of oxygen and suppress the geminate recombination of toxic carbon monoxide.

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