TY - JOUR
T1 - Biophysical and Mechanistic Models for Disease-Causing Protein Variants
AU - Stein, Amelie
AU - Fowler, Douglas M.
AU - Hartmann-Petersen, Rasmus
AU - Lindorff-Larsen, Kresten
PY - 2019/7
Y1 - 2019/7
N2 - The rapid decrease in DNA sequencing cost is revolutionizing medicine and science. In medicine, genome sequencing has revealed millions of missense variants that change protein sequences, yet we only understand the molecular and phenotypic consequences of a small fraction. Within protein science, high-throughput deep mutational scanning experiments enable us to probe thousands of variants in a single, multiplexed experiment. We review efforts that bring together these topics via experimental and computational approaches to determine the consequences of missense variants in proteins. We focus on the role of changes in protein stability as a driver for disease, and how experiments, biophysical models, and computation are providing a framework for understanding and predicting how changes in protein sequence affect cellular protein stability.
AB - The rapid decrease in DNA sequencing cost is revolutionizing medicine and science. In medicine, genome sequencing has revealed millions of missense variants that change protein sequences, yet we only understand the molecular and phenotypic consequences of a small fraction. Within protein science, high-throughput deep mutational scanning experiments enable us to probe thousands of variants in a single, multiplexed experiment. We review efforts that bring together these topics via experimental and computational approaches to determine the consequences of missense variants in proteins. We focus on the role of changes in protein stability as a driver for disease, and how experiments, biophysical models, and computation are providing a framework for understanding and predicting how changes in protein sequence affect cellular protein stability.
KW - computational biophysics
KW - deep mutational scanning
KW - genomics
KW - protein quality control
KW - protein stability
KW - variant classification
U2 - 10.1016/j.tibs.2019.01.003
DO - 10.1016/j.tibs.2019.01.003
M3 - Review
C2 - 30712981
AN - SCOPUS:85060866336
SN - 0968-0004
VL - 44
SP - 575
EP - 588
JO - Trends in Biochemical Sciences
JF - Trends in Biochemical Sciences
IS - 7
ER -