Protein promiscuity has been observed in many biological systems. These indiscriminate recognitions in molecular level increase the challenge of in silico study due to the large number of potential conformations. To investigate the recognition process in various peptides and the protein, we selected one essential breast-cancer-related domain, BRCA1-BRCT, as our model system. We used molecular dynamics simulations to carry out detailed analysis in dihedral space to study protein fluctuation and conformational changes upon the phosphopeptide binding. Also, the diffusion control association with phospho and non-phospho peptides is represented by Brownian dynamics with coarse-grained model. Our results show that BRCT is a preorganized domain and the residues around binding region can interact with phosphopeptides through moderate arrangement of backbone and sidechain angles. Although we traditionally expect binding reduces system flexibility, the non-polar phosphopeptide show more flexible in bound state and the new rotameric states come upon binding. The Brownian dynamics simulations illustrate how charged phospho group accelerate peptide diffusion. This work provides the insights into molecular recognition in promiscuous protein system.

Mechanistic insights into phosphopeptide–BRCT domain association: Preorganization, flexibility, and phosphate recognition

244th National Meeting (2012)

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