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

Paul, F 
Wehmeyer, C 
Abualrous, ET 
Wu, H 
Crabtree, MD 

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Understanding and control of structures and rates involved in protein-ligand binding are es- sential for drug design. Unfortunately, atomistic molecular dynamics (MD) simulations cannot di- rectly 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 timescales using simulations of an all-atom MD model, with high accuracy and pre- cision. 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 dissoci- ation 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.

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Biological physics, Chemical physics, Computational biophysics, Reaction kinetics and dynamics
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Nature Communications
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Springer Nature
Wellcome Trust (095195/Z/10/Z)
BBSRC (1348064)
Funding is acknowledged by European Commission (ERC StG “pcCells” to F.N.), Deutsche Forschungsgemeinschaft (SFB 1114/C3, SFB 740/D7, and TRR 186/A12 to F.N. and SFB 1114/A4 to F.N. and T.W.). J.C. is a Wellcome Trust Senior Research Fellow (WT 095195MA). J.S. is a Marie Sklodowska-Curie Internationally outgoing fellow. M.D.C. is supported by a Biotechnology and Biological Sciences Research Council (BBSRC) studentship.
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