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Reducing CDK4/6‐p16 INK4a interface. Computational alanine scanning of a peptide bound to CDK6 protein
Author(s) -
Villacañas Óscar,
RubioMartinez Jaime
Publication year - 2006
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.20943
Subject(s) - alanine scanning , cyclin dependent kinase 6 , peptide , alanine , chemistry , molecular dynamics , solvation , cell cycle , cell , cyclin dependent kinase , gene , biochemistry , solvent , amino acid , mutant , computational chemistry , mutagenesis
The tumor suppressor gene p16 INK4a is commonly found altered in numerous and different types of cancer. The encoded protein arrests cell cycle in G 1 phase by binding to CDK4 and CDK6, inhibiting their kinase function. In 1995, a 20‐residue peptide, extracted from p16 INK4a 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‐p16 INK4a 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. Proteins 2006. © 2006 Wiley‐Liss, Inc.