Computational and experimental studies of the interaction between phospho-peptides and the C-terminal domain of BRCA1 |
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Authors: | Anisimov Victor M Ziemys Arturas Kizhake Smitha Yuan Ziyan Natarajan Amarnath Cavasotto Claudio N |
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Institution: | (1) School of Biomedical Informatics, University of Texas Health Science Center at Houston, 7000 Fannin Ste. 690, Houston, TX 77030, USA;(2) Chemical Biology Program, Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX 77555, USA;(3) Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE 68198, USA;(4) Present address: The Methodist Hospital Research Institute, 6670 Bertner Ave., Houston, TX 77030, USA;(5) Present address: Kansas University Medical Center, Mailstop 4049, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA; |
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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. |
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