Protein-Protein Binding as a Two-Step Mechanism: Preselection of Encounter Poses during the Binding of BPTI and Trypsin.

Biophysical Journal
Ursula KahlerKlaus R Liedl

Abstract

Biomolecular recognition between proteins follows complex mechanisms, the understanding of which can substantially advance drug discovery efforts. Here, we track each step of the binding process in atomistic detail with molecular dynamics simulations using trypsin and its inhibitor bovine pancreatic trypsin inhibitor (BPTI) as a model system. We use umbrella sampling to cover a range of unbinding pathways. Starting from these simulations, we subsequently seed classical simulations at different stages of the process and combine them to a Markov state model. We clearly identify three kinetically separated states (an unbound state, an encounter state, and the final complex) and describe the mechanisms that dominate the binding process. From our model, we propose the following sequence of events. The initial formation of the encounter complex is driven by long-range interactions because opposite charges in trypsin and BPTI draw them together. The encounter complex features the prealigned binding partners with binding sites still partially surrounded by solvation shells. Further approaching leads to desolvation and increases the importance of van der Waals interactions. The native binding pose is adopted by maximizing short-range in...Continue Reading

Citations

Jan 26, 2021·Journal of Enzyme Inhibition and Medicinal Chemistry·Amanda Fernandes de MedeirosAna Heloneida de Araújo Morais
Mar 16, 2021·Journal of Chemical Information and Modeling·Johannes KramlKlaus R Liedl
May 8, 2021·Frontiers in Molecular Biosciences·Monica L Fernández-QuinteroKlaus R Liedl
Sep 14, 2021·Physical Chemistry Chemical Physics : PCCP·Zhenyu WangXiaolin Cheng
Sep 4, 2021·Proceedings of the National Academy of Sciences of the United States of America·Anna S KamenikBrian K Shoichet

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Methods Mentioned

BETA
x-ray
NMR

Software Mentioned

Molecular Operating Environment ( MOE )
PyEMMA
GIST
AmberTools
apo
cpptraj
PCCA
GIGIST
Protonate3D
LEaP

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