Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1

Victor M. Anisimov, Arturas Ziemys, Smitha Kizhake, Ziyan Yuan, Amarnath Natarajan, Claudio N. Cavasotto

Research output: Contribution to journalArticle

20 Citations (Scopus)

Abstract

The C-terminal domain of BRCA1(BRCT) is involved in the DNA repair pathway by recognizing the pSXXF motif in interacting proteins. It has been reported that short peptides containing this motif bind to BRCA1(BRCT) in the micromolar range with high specificity. In this work, the binding of pSXXF peptides has been studied computationally and experimentally in order to characterize their interaction with BRCA1(BRCT). Elucidation of the contacts that drive the protein-ligand interaction is critical for the development of high affinity small-molecule BRCA1 inhibitors. Molecular dynamics (MD) simulations revealed the key role of threonine at the peptide P+2 position in providing structural rigidity to the ligand in the bound state. The mutation at P+1 had minor effects. Peptide extension at the N-terminal position with the naphthyl amino acid exhibited a modest increase in binding affinity, what could be explained by the dispersion interaction of the naphthyl side-chain with a hydrophobic patch. Three in silico end-point methods were considered for the calculation of binding free energy. The Molecular Mechanics Poisson-Boltzmann Surface Area and the Solvated Interaction Energy methods gave reasonable agreement with experimental data, exhibiting a Pearlman predictive index of 0.71 and 0.78, respectively. The MM-quantum mechanics-surface area method yielded improved results, which was characterized by a Pearlman index of 0.78. The correlation coefficients were 0.59, 0.61 and 0.69, respectively. The ability to apply a QM level of theory within an end-point binding free energy protocol may provide a way for a consistent improvement of accuracy in computer-aided drug design.

Original languageEnglish (US)
Pages (from-to)1071-1084
Number of pages14
JournalJournal of Computer-Aided Molecular Design
Volume25
Issue number11
DOIs
StatePublished - Nov 1 2011

Fingerprint

Peptides
peptides
Mechanics
Free energy
Ligands
affinity
Computer-Aided Design
Molecular mechanics
Quantum theory
Drug Design
free energy
interactions
Threonine
Molecular Dynamics Simulation
proteins
Proteins
DNA Repair
Rigidity
Computer Simulation
ligands

Keywords

  • BRCA1
  • End-point binding free energy methods
  • MM-QMSA (MM/QM-COSMO)
  • Quantum mechanics
  • Semiempirical Hamiltonian

ASJC Scopus subject areas

  • Drug Discovery
  • Computer Science Applications
  • Physical and Theoretical Chemistry

Cite this

Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1. / Anisimov, Victor M.; Ziemys, Arturas; Kizhake, Smitha; Yuan, Ziyan; Natarajan, Amarnath; Cavasotto, Claudio N.

In: Journal of Computer-Aided Molecular Design, Vol. 25, No. 11, 01.11.2011, p. 1071-1084.

Research output: Contribution to journalArticle

Anisimov, Victor M. ; Ziemys, Arturas ; Kizhake, Smitha ; Yuan, Ziyan ; Natarajan, Amarnath ; Cavasotto, Claudio N. / Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1. In: Journal of Computer-Aided Molecular Design. 2011 ; Vol. 25, No. 11. pp. 1071-1084.
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