Beyond structural bioinformatics for genomics with dynamics characterization of an expanded KRAS mutational landscape. Comput Struct Biotechnol J 2023;21:4790-4803
Date
10/16/2023Pubmed ID
37841325Pubmed Central ID
PMC10570560DOI
10.1016/j.csbj.2023.10.003Scopus ID
2-s2.0-85173171942 (requires institutional sign-in at Scopus site)Abstract
Current capabilities in genomic sequencing outpace functional interpretations. Our previous work showed that 3D protein structure calculations enhance mechanistic understanding of genetic variation in sequenced tumors and patients with rare diseases. The KRAS GTPase is among the critical genetic factors driving cancer and germline conditions. Because KRAS-altered tumors frequently harbor one of three classic hotspot mutations, nearly all studies have focused on these mutations, leaving significant functional ambiguity across the broader KRAS genomic landscape observed in cancer and non-cancer diseases. Herein, we extend structural bioinformatics with molecular simulations to study an expanded landscape of 86 KRAS mutations. We identify multiple coordinated changes strongly associated with experimentally established KRAS biophysical and biochemical properties. The patterns we observe span hotspot and non-hotspot alterations, which can all dysregulate Switch regions, producing mutation-restricted conformations with different effector binding propensities. We experimentally measured mutation thermostability and identified shared and distinct patterns with simulations. Our results indicate mutation-specific conformations, which show potential for future research into how these alterations reverberate into different molecular and cellular functions. The data we present is not predictable using current genomic tools, demonstrating the added functional information derived from molecular simulations for interpreting human genetic variation.
Author List
Ratnasinghe BD, Haque N, Wagenknecht JB, Jensen DR, Valdivia Esparza GK, Leverence EN, Milech De Assuncao T, Mathison AJ, Lomberk G, Smith BC, Volkman BF, Urrutia R, Zimmermann MTAuthors
Gwen Lomberk PhD Professor in the Surgery department at Medical College of WisconsinAngela Mathison PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Thiago Milech De Assuncao Research Scientist II in the Surgery department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin
