title: Reducing CDK4/6-p16(INK4a) interface. Computational alanine scanning of a peptide bound to CDK6 protein.
abstract: The tumor suppressor gene p16INK4a is commonly found altered in numerous and different types of cancer. The encoded protein arrests cell cycle in G1 phase by binding to CDK4 and CDK6, inhibiting their kinase function. In 1995, a 20-residue peptide, extracted from p16INK4a protein sequence, was discovered that retains the cell cycle inhibition properties of the endogenous tumor suppressor. However, its structure has not been determined yet. In this article, the features of a theoretical structure of the peptide bound to CDK6 are reported. The complex was modeled from CDK6-p16INK4a X-ray crystal structure and through molecular dynamics. Final structure was assessed by comparing computed binding free energy changes, when single-alanine substitutions were brought about on the peptide, to experimental data. Better concordance was obtained when including a high level of solvation effects. Solute-solvent vdW energy and electrostatic energy between solute and first shells of water, computed through a force field and considering explicit waters, were also to be included to achieve reasonably good concordance between theoretical and experimental data.
authors.affiliation: Departament de Química Física, Universitat de Barcelona, Martí i Franquès 1, E-08028 Barcelona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Villacañas
authors.forename: Jaime
authors.initials: J
authors.lastname: Rubio-Martinez
mesh_terms: D000409:Alanine / Q000737:chemistry / Q000378:metabolism*; D001665:Binding Sites; D003198:Computer Simulation; D051358:Cyclin-Dependent Kinase 4 / Q000737:chemistry* / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000737:chemistry* / Q000378:metabolism*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D055672:Static Electricity; D040681:Structural Homology, Protein; D013816:Thermodynamics; D014867:Water
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D014867:Water; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D000409:Alanine