Biophysical Simulations and Structure-Based Modeling of Residue Interaction Networks in the Tumor Suppressor Proteins Reveal Functional Role of Cancer Mutation Hotspots in Molecular Communication

Publication date: Available online 16 October 2018Source: Biochimica et Biophysica Acta (BBA) - General SubjectsAuthor(s): Gennady M. VerkhivkerAbstractIn the current study, we have combined molecular simulations and energetic analysis with dynamics-based network modeling and perturbation response scanning to determine molecular signatures of mutational hotspot residues in the p53, PTEN, and SMAD4 tumor suppressor proteins. By examining structure, energetics and dynamics of these proteins, we have shown that inactivating mutations preferentially target a group of structurally stable residues that play a fundamental role in global propagation of dynamic fluctuations and mediating allosteric interaction networks. Through integration of long-range perturbation dynamics and network-based approaches, we have quantified allosteric potential of residues in the studied proteins. The results have revealed that mutational hotspot sites often correspond to high centrality mediating centers of the residue interaction networks that are responsible for coordination of global dynamic changes and allosteric signaling. Our findings have also suggested that structurally stable mutational hotpots can act as major effectors of allosteric interactions and mutations in these positions are typically associated with severe phenotype. Modeling of shortest inter-residue pathways has shown that mutational hotspot sites can also serve as key mediating bridges of allosteric communication in the p53 and P...
Source: Biochimica et Biophysica Acta (BBA) General Subjects - Category: Biochemistry Source Type: research