Wrapping Effects within a Proposed Function-Rescue Strategy for the Y220C Oncogenic Mutation of Protein p53

• Autores: Accordino, Sebastián Roberto; Rodríguez Fris, Jorge Ariel; Appignanesi, Gustavo Adrian
• Año de publicación: 2013
• Idioma: inglés
• Tipo de recurso: artículo
• Materia: PROTEINS; BINDING; DRUG DESIGN; P53
• Institución: Consejo Nacional de Investigaciones Científicas y Técnicas

Soluble proteins must protect their structural integrity from water attack by wrapping interactions which imply the clustering of nonpolar residues around the backbone hydrogen bonds. Thus, poorly wrapped hydrogen bonds constitute defects which have been identified as promoters of protein associations since they favor the removal of hydrating molecules. More specifically, a recent study of our group has shown that wrapping interactions allow the successful identification of protein binding hot spots. Additionally, we have also shown that drugs disruptive of protein-protein interfaces tend to mimic the wrapping behavior of the protein they replace. Within this context, in this work we study wrapping three body interactions related to the oncogenic Y220C mutation of the tumor suppressor protein p53. Our computational results rationalize the oncogenic nature of the Y220C mutation, explain the binding of a drug-like molecule already designed to restore the function of p53 and provide clues to help improve this function-rescue strategy and to apply in other drug design or re-engineering techniques.
Fil: Accordino, Sebastián Roberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Química del Sur; Argentina.;
Fil: Rodríguez Fris, Jorge Ariel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Química del Sur; Argentina.;
Fil: Appignanesi, Gustavo Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico CONICET Bahía Blanca. Instituto de Química del Sur; Argentina.;