title: Exact low-force kinetics from high-force single-molecule unfolding events.
abstract: 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.
authors: Department of Chemistry, Center for Computational Medicine and Biology, University of Michigan, Ann Arbor, Michigan, USA.
authors: Jeremiah
authors: J
authors: Nummela
authors: Ioan
authors: I
authors: Andricioaei
mesh_terms: 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
chemical_list: D008024:Ligands; D010455:Peptides; D012313:RNA; D000409:Alanine
references: Phys Rev Lett. 2006 Jun 2;96(21):218301
references: 16803276
references: Nat Struct Biol. 2002 Sep;9(9):646-52
references: 12198485
references: Proc Natl Acad Sci U S A. 2000 May 23;97(11):5877-82
references: 10801977
references: Proc Natl Acad Sci U S A. 2002 May 14;99(10):6731-6
references: 11997475
references: Biophys J. 2003 Jul;85(1):5-15
references: 12829459
references: Phys Rev Lett. 2006 Mar 17;96(10):108101
references: 16605793
references: Biophys J. 2005 Sep;89(3):1612-20
references: 15994895
references: Science. 2002 Jun 7;296(5574):1832-5
references: 12052949
references: Science. 2001 Apr 27;292(5517):733-7
references: 11326101
references: Acc Chem Res. 2005 Jul;38(7):504-13
references: 16028884
references: Biophys J. 2005 May;88(5):3224-42
references: 15764661
references: Nature. 2003 Mar 27;422(6930):446-9
references: 12660787
references: Curr Opin Struct Biol. 2001 Apr;11(2):224-30
references: 11297932
references: Proc Natl Acad Sci U S A. 2000 Aug 29;97(18):9972-7
references: 10963664
references: Biophys J. 2000 Sep;79(3):1206-12
references: 10968985
references: Proc Natl Acad Sci U S A. 2001 Mar 27;98(7):3658-61
references: 11274384
references: J Mol Biol. 1999 May 7;288(3):441-59
references: 10329153
references: Phys Rev E Stat Nonlin Soft Matter Phys. 2001 Jan;63(1 Pt 2):016702
references: 11304388
references: Nature. 1999 Jan 7;397(6714):50-3
references: 9892352
references: Proc Natl Acad Sci U S A. 1999 Mar 30;96(7):3694-9
references: 10097099
references: J Chem Phys. 2005 Aug 15;123(7):074107
references: 16229559
references: Phys Chem Chem Phys. 2006 Aug 28;8(32):3692-706
references: 16896432
references: Nature. 2003 Jan 23;421(6921):423-7
references: 12540915
references: Biophys J. 2001 Sep;81(3):1324-32
references: 11509348
references: J Chem Phys. 2005 Jun 15;122(23):234915
references: 16008495
references: Q Rev Biophys. 1991 Aug;24(3):227-91
references: 1749823
references: Acc Chem Res. 2002 Jun;35(6):325-31
references: 12069616
references: Proc Natl Acad Sci U S A. 2000 Jun 6;97(12):6521-6
references: 10823892