Assessment of mutation probabilities of KRAS G12 missense mutants and their long-timescale dynamics by atomistic molecular simulations and Markov state modeling

• DOI: 10.1371/journal.pcbi.1006458
• Publication Date: 2018-09-10T17:23:06Z
• Authors: Tatu Pantsar; Sami Rissanen; Daniel Dauch; Tuomo Laitinen; Ilpo Vattulainen; Antti Poso
• Keywords: STRUCTURAL BASIS; 0301 basic medicine; QH301-705.5; DNA Mutational Analysis; NOONAN-SYNDROME; Molecular Conformation; Mutation, Missense; 610; 8-OXOGUANINE DNA GLYCOSYLASE; Molecular Dynamics Simulation; Ligands; 114 Physical sciences; Guanosine Diphosphate; 114; Proto-Oncogene Proteins p21(ras); EFFECTOR-BINDING SITE; 03 medical and health sciences; N-RAS; HYPERVARIABLE REGION; Neoplasms; Humans; CRYSTAL-STRUCTURE; Biology (General); Biochemistry, cell and molecular biology; Probability; Principal Component Analysis; Computer and information sciences; ACTIVE-SITE; Markov Chains; 3. Good health; Genes, ras; NMR-SPECTROSCOPY; Mutation; Guanosine Triphosphate; K-RAS; Hydrophobic and Hydrophilic Interactions; Research Article

A mutated KRAS protein is frequently observed in human cancers. Traditionally, the oncogenic properties of missense mutants at position 12 (G12X) have been considered as equal. Here, by assessing probabilities occurrence all G12X mutations and dynamics we show that this assumption does not hold true. Instead, our findings revealed an outstanding mutational bias. We conducted a thorough analysis assessed to what extent mutation frequencies follow random distribution. Unique tissue-specific are displayed with specific mutations, especially G12R, which cannot be explained probabilities. To clarify underlying causes for nonrandom probabilities, extensive atomistic molecular simulations (170 μs) study differences on level. The allosteric hydrophobic signaling network KRAS, altered among such differs from wild-type mutation-specific. shift long-timescale conformational was confirmed Markov state modeling. found modify way, manifested switch regions responsible effector binding. provide basis understand better consequences mutations.