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Protein-Protein Binding as a Two-Step Mechanism: Preselection of Encounter Poses during the Binding of BPTI and Trypsin
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...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Biophysical Society
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399559/ https://www.ncbi.nlm.nih.gov/pubmed/32697976 http://dx.doi.org/10.1016/j.bpj.2020.06.032 |
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author | Kahler, Ursula Kamenik, Anna S. Waibl, Franz Kraml, Johannes Liedl, Klaus R. |
author_facet | Kahler, Ursula Kamenik, Anna S. Waibl, Franz Kraml, Johannes Liedl, Klaus R. |
author_sort | Kahler, Ursula |
collection | PubMed |
description | 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 interactions. Thereby side-chain rearrangements ensure optimal shape complementarity. In particular, BPTI’s P1 residue adapts to the S1 pocket and prime site residues reorient to optimize interactions. After the paradigm of conformation selection, binding-competent conformations of BPTI and trypsin are already present in the apo ensembles and their probabilities increase during this proposed two-step association process. This detailed characterization of the molecular forces driving the binding process includes numerous aspects that have been discussed as central to the binding of trypsin and BPTI and protein complex formation in general. In this study, we combine all these aspects into one comprehensive model of protein recognition. We thereby contribute to enhance our general understanding of this fundamental mechanism, which is particularly critical as the development of biopharmaceuticals continuously gains significance. |
format | Online Article Text |
id | pubmed-7399559 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | The Biophysical Society |
record_format | MEDLINE/PubMed |
spelling | pubmed-73995592020-10-10 Protein-Protein Binding as a Two-Step Mechanism: Preselection of Encounter Poses during the Binding of BPTI and Trypsin Kahler, Ursula Kamenik, Anna S. Waibl, Franz Kraml, Johannes Liedl, Klaus R. Biophys J Articles 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 interactions. Thereby side-chain rearrangements ensure optimal shape complementarity. In particular, BPTI’s P1 residue adapts to the S1 pocket and prime site residues reorient to optimize interactions. After the paradigm of conformation selection, binding-competent conformations of BPTI and trypsin are already present in the apo ensembles and their probabilities increase during this proposed two-step association process. This detailed characterization of the molecular forces driving the binding process includes numerous aspects that have been discussed as central to the binding of trypsin and BPTI and protein complex formation in general. In this study, we combine all these aspects into one comprehensive model of protein recognition. We thereby contribute to enhance our general understanding of this fundamental mechanism, which is particularly critical as the development of biopharmaceuticals continuously gains significance. The Biophysical Society 2020-08-04 2020-07-10 /pmc/articles/PMC7399559/ /pubmed/32697976 http://dx.doi.org/10.1016/j.bpj.2020.06.032 Text en © 2020 Biophysical Society. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Articles Kahler, Ursula Kamenik, Anna S. Waibl, Franz Kraml, Johannes Liedl, Klaus R. Protein-Protein Binding as a Two-Step Mechanism: Preselection of Encounter Poses during the Binding of BPTI and Trypsin |
title | Protein-Protein Binding as a Two-Step Mechanism: Preselection of Encounter Poses during the Binding of BPTI and Trypsin |
title_full | Protein-Protein Binding as a Two-Step Mechanism: Preselection of Encounter Poses during the Binding of BPTI and Trypsin |
title_fullStr | Protein-Protein Binding as a Two-Step Mechanism: Preselection of Encounter Poses during the Binding of BPTI and Trypsin |
title_full_unstemmed | Protein-Protein Binding as a Two-Step Mechanism: Preselection of Encounter Poses during the Binding of BPTI and Trypsin |
title_short | Protein-Protein Binding as a Two-Step Mechanism: Preselection of Encounter Poses during the Binding of BPTI and Trypsin |
title_sort | protein-protein binding as a two-step mechanism: preselection of encounter poses during the binding of bpti and trypsin |
topic | Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7399559/ https://www.ncbi.nlm.nih.gov/pubmed/32697976 http://dx.doi.org/10.1016/j.bpj.2020.06.032 |
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