Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex

We present a novel steered molecular dynamics scheme to induce the dissociation of large protein-protein complexes. We apply this scheme to study the interaction of a T cell receptor (TCR) with a major histocompatibility complex (MHC) presenting a peptide (p). Two TCR-pMHC complexes are considered,...

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Asıl Yazarlar: Cuendet, Michel A., Michielin, Olivier
Materyal Türü: Makale
Dil:English
Baskı/Yayın Bilgisi: The Biophysical Society 2008
Konular:
Biophysical Theory and Modeling
Online Erişim:https://ncbi.nlm.nih.gov/pmc/articles/PMC2553100/
https://ncbi.nlm.nih.gov/pubmed/18621828
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1529/biophysj.108.131383
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spelling pubmed-25531002009-10-15 Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex Cuendet, Michel A. Michielin, Olivier Biophys J Biophysical Theory and Modeling We present a novel steered molecular dynamics scheme to induce the dissociation of large protein-protein complexes. We apply this scheme to study the interaction of a T cell receptor (TCR) with a major histocompatibility complex (MHC) presenting a peptide (p). Two TCR-pMHC complexes are considered, which only differ by the mutation of a single amino acid on the peptide; one is a strong agonist that produces T cell activation in vivo, while the other is an antagonist. We investigate the interaction mechanism from a large number of unbinding trajectories by analyzing van der Waals and electrostatic interactions and by computing energy changes in proteins and solvent. In addition, dissociation potentials of mean force are calculated with the Jarzynski identity, using an averaging method developed for our steering scheme. We analyze the convergence of the Jarzynski exponential average, which is hampered by the large amount of dissipative work involved and the complexity of the system. The resulting dissociation free energies largely underestimate experimental values, but the simulations are able to clearly differentiate between wild-type and mutated TCR-pMHC and give insights into the dissociation mechanism. The Biophysical Society 2008-10-15 2008-07-11 /pmc/articles/PMC2553100/ /pubmed/18621828 http://dx.doi.org/10.1529/biophysj.108.131383 Text en Copyright © 2008, Biophysical Society
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Biophysical Theory and Modeling
spellingShingle Biophysical Theory and Modeling
Cuendet, Michel A.
Michielin, Olivier
Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex
description We present a novel steered molecular dynamics scheme to induce the dissociation of large protein-protein complexes. We apply this scheme to study the interaction of a T cell receptor (TCR) with a major histocompatibility complex (MHC) presenting a peptide (p). Two TCR-pMHC complexes are considered, which only differ by the mutation of a single amino acid on the peptide; one is a strong agonist that produces T cell activation in vivo, while the other is an antagonist. We investigate the interaction mechanism from a large number of unbinding trajectories by analyzing van der Waals and electrostatic interactions and by computing energy changes in proteins and solvent. In addition, dissociation potentials of mean force are calculated with the Jarzynski identity, using an averaging method developed for our steering scheme. We analyze the convergence of the Jarzynski exponential average, which is hampered by the large amount of dissipative work involved and the complexity of the system. The resulting dissociation free energies largely underestimate experimental values, but the simulations are able to clearly differentiate between wild-type and mutated TCR-pMHC and give insights into the dissociation mechanism.
author Cuendet, Michel A.
Michielin, Olivier
author_facet Cuendet, Michel A.
Michielin, Olivier
author_sort Cuendet, Michel A.
title Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex
title_short Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex
title_full Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex
title_fullStr Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex
title_full_unstemmed Protein-Protein Interaction Investigated by Steered Molecular Dynamics: The TCR-pMHC Complex
title_sort protein-protein interaction investigated by steered molecular dynamics: the tcr-pmhc complex
publisher The Biophysical Society
publisher_facet The Biophysical Society
publishDate 2008
url https://ncbi.nlm.nih.gov/pmc/articles/PMC2553100/
https://ncbi.nlm.nih.gov/pubmed/18621828
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1529/biophysj.108.131383
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