title: SEEKR: Simulation Enabled Estimation of Kinetic Rates, A Computational Tool to Estimate Molecular Kinetics and Its Application to Trypsin-Benzamidine Binding.
abstract: We present the Simulation Enabled Estimation of Kinetic Rates (SEEKR) package, a suite of open-source scripts and tools designed to enable researchers to perform multiscale computation of the kinetics of molecular binding, unbinding, and transport using a combination of molecular dynamics, Brownian dynamics, and milestoning theory. To demonstrate its utility, we compute the kon, koff, and ΔGbindfor the protein trypsin with its noncovalent binder, benzamidine, and examine the kinetics and other results generated in the context of the new software, and compare our findings to previous studies performed on the same system. We compute a konestimate of (2.1 ± 0.3) × 107M-1s-1, a koffestimate of 83 ± 14 s-1, and a ΔGbindof -7.4 ± 0.1 kcal·mol-1, all of which compare closely to the experimentally measured values of 2.9 × 107M-1s-1, 600 ± 300 s-1, and -6.71 ± 0.05 kcal·mol-1, respectively.
authors.affiliation: Laufer Center for Physical and Quantitative Biology, Stony Brook University , Stony Brook, New York 11794, United States.|University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Lane W
authors.identifier: 0000-0002-0865-5867
authors.initials: LW
authors.lastname: Votapka
authors.affiliation: University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Jagger
authors.affiliation: University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Alexandra L
authors.initials: AL
authors.lastname: Heyneman
authors.affiliation: University of California San Diego , 9500 Gilman Drive, La Jolla, California 92093, United States.
authors.forename: Rommie E
authors.identifier: 0000-0002-9275-9553
authors.initials: RE
authors.lastname: Amaro
mesh_terms: D001550:Benzamidines / Q000737:chemistry*; D001665:Binding Sites; D007700:Kinetics; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D014357:Trypsin / Q000737:chemistry* / Q000378:metabolism
chemical_list: D001550:Benzamidines; D014357:Trypsin; C032157:benzamidine