Albany 2015:Book of Abstracts

Albany 2015
Conversation 19
June 9-13 2015
©Adenine Press (2012)

Multiscale Estimation of Binding Kinetics Using Molecular Dynamics, Brownian Dynamics, and Milestoning

Estimating kinetics is an important and challenging task in computational biophysics. The kinetic rate constants of ligand-receptor interactions, in particular the kon and koffvalues, play an important role in enzymology (Bar-Even et al., 2011) and drug discovery (Copeland et al., 2007), where the kinetic rate constants of ligand-receptor association and dissociation are important determinants of drug efficacy (Copeland et al., 2007), Although these values may often be measured experimentally, an accurate computational estimate would be attractive in cases where experimental measurement is expensive or difficult. In addition, advances in computational power, particularly in parallel computing, offer great potential for methods that take advantage of the vast and increasing power of computation. In this work, the kinetic rate constants of binding were estimated for four biochemically relevant molecular systems by a novel method that combines Brownian dynamics simulations with more detailed molecular dynamics simulations using milestoning theory. The rate constants found using this method were in good agreement with experimentally and theoretically obtained values. We predicted the association rate of a small charged molecule toward both a charged and an uncharged sphere and verified the estimated value with Smoluchowski theory. We also calculated the kon rate constant for superoxide dismutase with its natural substrate, O2-, in a validation of a previous experiment using similar methods but with a number of important improvements. Finally, we calculated the kon for Troponin C with its natural substrate Ca2+. The kon calculated for both systems closely resemble experimentally obtained values. This novel multiscale approach is computationally cheaper and more parallelizable compared to other methods of similar accuracy. We anticipate that this methodology will be useful for predicting kinetic rate constants and for understanding the process of binding between a small molecule and a protein receptor. amaro.gif This research has been supported by NIH Director's New Innovator Award DP2-OD007237 and XSEDE RAC CHE060073N to REA, and a NSF Graduate Research Fellowship to LWV. References
    Bar-Even A, Noor E, Savir Y, Liebermeister W, Davidi D, et al. (2011) The Moderately Efficient Enzyme: Evolutionary and Physicochemical Trends Shaping Enzyme Parameters. Biochemistry 50: 4402-4410.

    Copeland RA, Pompliano DL, Meek TD (2007) Drug-target residence time and its implications for lead optimization (vol 5, pg 730, 2006). Nature Reviews Drug Discovery 6: 249-249.

Lane W. Votapka
Rommie E. Amaro

Department of Chemistry and Biochemistry
University of California, San Diego
La Jolla, CA 92093

Ph: (858) 534-9629