Exact low-force kinetics from high-force single-molecule unfolding events.
Mechanical forces play a key role in crucial cellular processes involving force-bearing biomolecules, as well as in novel single-molecule pulling experiments. We present an exact method that enables one to extrapolate, to low (or zero) forces, entire time-correlation functions and kinetic rate constants from the conformational dynamics either simulated numerically or measured experimentally at a single, relatively higher, external force. The method has twofold relevance: 1), to extrapolate the kinetics at physiological force conditions from molecular dynamics trajectories generated at higher forces that accelerate conformational transitions; and 2), to extrapolate unfolding rates from experimental force-extension single-molecule curves. The theoretical formalism, based on stochastic path integral weights of Langevin trajectories, is presented for the constant-force, constant loading rate, and constant-velocity modes of the pulling experiments. For the first relevance, applications are described for simulating the conformational isomerization of alanine dipeptide; and for the second relevance, the single-molecule pulling of RNA is considered. The ability to assign a weight to each trace in the single-molecule data also suggests a means to quantitatively compare unfolding pathways under different conditions.
Nummela
Jeremiah
J
Department of Chemistry, Center for Computational Medicine and Biology, University of Michigan, Ann Arbor, Michigan, USA.
Andricioaei
Ioan
I
D000409:Alanine / Q000737:chemistry; D001703:Biophysics / Q000379:methods*; D002448:Cell Adhesion; D007700:Kinetics; D008024:Ligands; D015233:Models, Statistical; D008962:Models, Theoretical; D008968:Molecular Conformation; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D011489:Protein Denaturation; D012313:RNA / Q000737:chemistry; D013269:Stochastic Processes; D013314:Stress, Mechanical
D008024:Ligands; D010455:Peptides; D012313:RNA; D000409:Alanine
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