PMID- 28723223
OWN - NLM
STAT- MEDLINE
DCOM- 20180430
LR  - 20210115
IS  - 1549-9626 (Electronic)
IS  - 1549-9618 (Linking)
VI  - 13
IP  - 9
DP  - 2017 Sep 12
TI  - Free Energy of Binding and Mechanism of Interaction for the MEEVD-TPR2A 
      Peptide-Protein Complex.
PG  - 4514-4523
LID - 10.1021/acs.jctc.7b00105 [doi]
AB  - The association between the MEEVD C-terminal peptide from the heat shock protein 
      90 (Hsp90) and tetratricopeptide repeat A (TPR2A) domain of the heat shock 
      organizing protein (Hop) is a useful prototype to study the fundamental molecular 
      details about the Hop-Hsp90 interaction. We study here the mechanism of 
      binding/unbinding and compute the standard binding free energy and potential of 
      mean force for the association of the MEEVD peptide to the TPR2A domain using the 
      Adaptive Biasing Force (ABF) methodology. We observe conformational changes of 
      the peptide and the protein receptor induced by binding. We measure the binding 
      free energy of -8.4 kcal/mol, which is consistent with experimental estimates. 
      The simulations achieve multiple unbinding and rebinding events along a 
      consistent pathway connecting the binding site to solvent. The MEEVD peptide 
      slowly dissociates disrupting the hydrogen bonds first, then tilting on the side 
      while preserving the interaction with the side chain of residue Asp 5 of the 
      peptide. After this initial displacement, the peptide completely dissociates and 
      moves into the solvent. Rebinding of the MEEVD peptide from the solvent to the 
      receptor binding site occurs slowly through the portal of entry. Unbinding and 
      rebinding go through intermediate states characterized by the peptide interacting 
      with a lateral helix, helix A1, of the receptor with mainly Asp 5, Val 4, and Glu 
      3 of the peptide. This newly discovered intermediate structure is characterized 
      by numerous contacts with the receptor which lead to complete formation of the 
      bound complex. The structure of the bound complex obtained after rebinding is 
      structurally very similar to the crystal structure of the complex (0.48 A 
      root-mean square deviation). The residues Asp 5, Val 4, and Glu 3 adopt 
      conformations and intermolecular contacts with excellent structural similarity 
      with the native ones. Finally, the dissociation and reassociation of MEEVD induce 
      hydration/dehydration transitions, which provide insights on the role of 
      desolvation and solvation processes in protein-peptide binding.
FAU - Lapelosa, Mauro
AU  - Lapelosa M
AUID- ORCID: 0000-0003-1377-9562
AD  - Department of Drug Discovery and Development, Italian Institute of Technology , 
      Via Morego 30, Genova 16163, Italy.
LA  - eng
PT  - Journal Article
DEP - 20170803
PL  - United States
TA  - J Chem Theory Comput
JT  - Journal of chemical theory and computation
JID - 101232704
RN  - 0 (HOPX protein, human)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (Homeodomain Proteins)
RN  - 0 (Oligopeptides)
RN  - 0 (Tumor Suppressor Proteins)
SB  - IM
MH  - HSP90 Heat-Shock Proteins/chemistry/*metabolism
MH  - Homeodomain Proteins/chemistry/*metabolism
MH  - Humans
MH  - Molecular Docking Simulation
MH  - Molecular Dynamics Simulation
MH  - Oligopeptides/chemistry/*metabolism
MH  - Protein Binding
MH  - Protein Conformation
MH  - Tetratricopeptide Repeat
MH  - *Thermodynamics
MH  - Tumor Suppressor Proteins/chemistry/*metabolism
EDAT- 2017/07/21 06:00
MHDA- 2018/05/01 06:00
CRDT- 2017/07/21 06:00
PHST- 2017/07/21 06:00 [pubmed]
PHST- 2018/05/01 06:00 [medline]
PHST- 2017/07/21 06:00 [entrez]
AID - 10.1021/acs.jctc.7b00105 [doi]
PST - ppublish
SO  - J Chem Theory Comput. 2017 Sep 12;13(9):4514-4523. doi: 10.1021/acs.jctc.7b00105. 
      Epub 2017 Aug 3.