Repository: Freie Universität Berlin, Math Department

Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations

Paul, F. and Wehmeyer, C. and Abualrous, E. T. and Wu, H. and Crabtree, M. D. and Schöneberg, J. and Clarke, J. and Freund, C. and Weikl, T. and Noé, F. (2017) Protein-peptide association kinetics beyond the seconds timescale from atomistic simulations. Nat. Comm., 8 (1095).


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Understanding and control of structures and rates involved in protein ligand binding are essential for drug design. Unfortunately, atomistic molecular dynamics (MD) simulations cannot directly sample the excessively long residence and rearrangement times of tightly binding complexes. Here we exploit the recently developed multi-ensemble Markov model framework to compute full protein-peptide kinetics of the oncoprotein fragment 25-109Mdm2 and the nano-molar inhibitor peptide PMI. Using this system, we report, for the first time, direct estimates of kinetics beyond the seconds timescale using simulations of an all-atom MD model, with high accuracy and precision. These results only require explicit simulations on the sub-milliseconds timescale and are tested against existing mutagenesis data and our own experimental measurements of the dissociation and association rates. The full kinetic model reveals an overall downhill but rugged binding funnel with multiple pathways. The overall strong binding arises from a variety of conformations with different hydrophobic contact surfaces that interconvert on the milliseconds timescale.

Item Type:Article
Subjects:Physical Sciences
Physical Sciences > Chemistry
Physical Sciences > Chemistry > Physical Chemistry
Mathematical and Computer Sciences
Divisions:Department of Mathematics and Computer Science > Institute of Mathematics > Comp. Molecular Biology
ID Code:2173
Deposited By: BioComp Admin
Deposited On:29 Dec 2017 13:09
Last Modified:16 Feb 2018 14:53

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