Molecular modeling and molecular dynamic simulation of the effects of variants in the TGFBR2 kinase domain as a paradigm for interpretation of variants obtained by next generation sequencing.
Variants in the TGFBR2 kinase domain cause several human diseases and can increase propensity for cancer. The widespread application of next generation sequencing within the setting of Individualized Medicine (IM) is increasing the rate at which TGFBR2 kinase domain variants are being identified. However, their clinical relevance is often uncertain. Consequently, we sought to evaluate the use of molecular modeling and molecular dynamics (MD) simulations for assessing the potential impact of variants within this domain. We documented the structural differences revealed by these models across 57 variants using independent MD simulations for each. Our simulations revealed various mechanisms by which variants may lead to functional alteration; some are revealed energetically, while others structurally or dynamically. We found that the ATP binding site and activation loop dynamics may be affected by variants at positions throughout the structure. This prediction cannot be made from the linear sequence alone. We present our structure-based analyses alongside those obtained using several commonly used genomics-based predictive algorithms. We believe the further mechanistic information revealed by molecular modeling will be useful in guiding the examination of clinically observed variants throughout the exome, as well as those likely to be discovered in the near future by clinical tests leveraging next-generation sequencing through IM efforts.
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America.
Michael T
http://orcid.org/0000-0001-7073-0525
MT
Zimmermann
Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Mayo Clinic, Rochester, Minnesota, United States of America.|Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, United States of America.|Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, United States of America.
Raul
R
Urrutia
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States of America.
Gavin R
GR
Oliver
Center for Individualized Medicine, Mayo Clinic, Jacksonville, FL, United States of America.
Patrick R
http://orcid.org/0000-0003-0658-1275
PR
Blackburn
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States of America.
Margot A
MA
Cousin
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States of America.
Nicole J
NJ
Bozeck
Department of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN, United States of America.|Center for Individualized Medicine, Mayo Clinic, Rochester, MN, United States of America.
Eric W
EW
Klee
D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D056004:Molecular Dynamics Simulation; D000072417:Protein Domains; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000235:genetics*; D017433:Protein Structure, Secondary; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry* / Q000235:genetics*
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II