Mapping the Conformation Space of Wildtype and Mutant H-Ras with a Memetic, Cellular, and Multiscale Evolutionary Algorithm

PLoS Computational Biology
Rudy ClausenAmarda Shehu

Abstract

An important goal in molecular biology is to understand functional changes upon single-point mutations in proteins. Doing so through a detailed characterization of structure spaces and underlying energy landscapes is desirable but continues to challenge methods based on Molecular Dynamics. In this paper we propose a novel algorithm, SIfTER, which is based instead on stochastic optimization to circumvent the computational challenge of exploring the breadth of a protein's structure space. SIfTER is a data-driven evolutionary algorithm, leveraging experimentally-available structures of wildtype and variant sequences of a protein to define a reduced search space from where to efficiently draw samples corresponding to novel structures not directly observed in the wet laboratory. The main advantage of SIfTER is its ability to rapidly generate conformational ensembles, thus allowing mapping and juxtaposing landscapes of variant sequences and relating observed differences to functional changes. We apply SIfTER to variant sequences of the H-Ras catalytic domain, due to the prominent role of the Ras protein in signaling pathways that control cell proliferation, its well-studied conformational switching, and abundance of documented mutati...Continue Reading

References

Jun 2, 1992·Biochemistry·C K FoleyM W Anderson
Jan 1, 1987·Annual Review of Biochemistry·M Barbacid
Nov 5, 1997·Proteins·B L de GrootH J Berendsen
Oct 29, 1997·Proceedings of the National Academy of Sciences of the United States of America·J Ma, M Karplus
Jul 1, 1999·Protein Science : a Publication of the Protein Society·C J TsaiR Nussinov
Sep 1, 1999·Proceedings of the National Academy of Sciences of the United States of America·C J TsaiR Nussinov
Oct 3, 1999·Protein Engineering·B MaR Nussinov
Apr 26, 2001·Proceedings of the National Academy of Sciences of the United States of America·M SpoernerA Wittinghofer
Nov 10, 2001·Science·I R Vetter, A Wittinghofer
Dec 26, 2001·Nucleic Acids Research·Ada HamoshVictor A McKusick
Sep 6, 2002·Proceedings of the National Academy of Sciences of the United States of America·Brian E HallNicolas Nassar
Nov 25, 2003·Nature Structural Biology·Helen BermanHaruki Nakamura
Jul 23, 2004·The Journal of Chemical Physics·Donald HamelbergJ Andrew McCammon
May 5, 2005·Proceedings of the National Academy of Sciences of the United States of America·M Karplus, J Kuriyan
May 10, 2005·The Journal of Biological Chemistry·Bradley FordNicolas Nassar
Nov 11, 2005·Physical Biology·Stephen WellsM F Thorpe
Mar 15, 2006·Structure·Bradley FordNicolas Nassar
Jul 18, 2006·Current Topics in Medicinal Chemistry·Nicolas NassarYi Zheng
Dec 13, 2006·Biophysical Journal·Amarda ShehuCecilia Clementi
Apr 13, 2007·Biochimica Et Biophysica Acta·Krishnaraj RajalingamStefan Albert
Jun 24, 2008·Nature Reviews. Molecular Cell Biology·Antoine E Karnoub, Robert A Weinberg
Sep 6, 2008·Biochemistry·Casey O'Connor, Evgenii L Kovrigin
Sep 25, 2008·Evolutionary Computation·Ole J Mengshoel, David E Goldberg
Oct 21, 2009·Nature Chemical Biology·David D BoehrPeter E Wright
Mar 3, 2010·Proceedings of the National Academy of Sciences of the United States of America·Greg BuhrmanCarla Mattos
Mar 20, 2010·Biochemistry·Kristian W KaufmannJens Meiler
Sep 15, 2010·PLoS Computational Biology·Suryani LukmanJ Andrew McCammon
Mar 31, 2011·Database : the Journal of Biological Databases and Curation·Michele Magrane, Uniprot Consortium
Nov 3, 2011·PloS One·Barry J GrantAlemayehu A Gorfe
Jan 15, 2013·Journal of Chemical Theory and Computation·Julie Baussand, Jens Kleinjung
Sep 26, 2013·Methods in Molecular Biology·Stephen A Wells
Oct 8, 2013·Journal of Computational Biology : a Journal of Computational Molecular Cell Biology·Fengzhu Sun
May 20, 2014·Current Opinion in Structural Biology·Rommie E Amaro, Manju Bansal
Feb 17, 2015·Structure·Susan K FeticsCarla Mattos
Apr 17, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Kendra Marcus, Carla Mattos

❮ Previous
Next ❯

Citations

Jan 8, 2016·Chemical Reviews·Andre A S T Ribeiro, Vanessa Ortiz
Jan 28, 2016·Chemical Reviews·Shaoyong LuJian Zhang
Jul 12, 2016·Chemical Society Reviews·Shaoyong LuRuth Nussinov
Jan 24, 2017·IEEE/ACM Transactions on Computational Biology and Bioinformatics·Emmanuel SapinAmarda Shehu
Apr 29, 2016·PLoS Computational Biology·Tatiana MaximovaAmarda Shehu
Sep 16, 2020·Physical Chemistry Chemical Physics : PCCP·Jianzhong ChenWeiliang Zhu
Jun 7, 2019·BMC Bioinformatics·David MorrisAmarda Shehu
Mar 8, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Fardina Fathmiul AlamAmarda Shehu
Aug 19, 2016·BMC Genomics·Emmanuel SapinAmarda Shehu
Mar 7, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Taseef RahmanAmarda Shehu

❮ Previous
Next ❯

Methods Mentioned

BETA
GTPase
nucleotide exchange
PCA
NMR
Rosetta

Software Mentioned

AMBER SIfTER
Pymol
AMBER
LAPACK
CONCOORD
imshow
SIfTER
SIfTERnow
TIFF
FRODA

Related Concepts

Related Feeds

Birth Defects

Birth defects encompass structural and functional alterations that occur during embryonic or fetal development and are present since birth. The cause may be genetic, environmental or unknown and can result in physical and/or mental impairment. Here is the latest research on birth defects.

Addison Disease

Addison's disease, also known as primary adrenal insufficiency and hypocortisolism, is a long-term endocrine disorder in which the adrenal glands do not produce enough steroid hormones. Discover the latest research on Addison's disease here.

Alzheimer's Disease: Genetics

Alzheimer's disease is a neurodegenerative disease. Discover genetic and epigenetic aspects of Alzheimer’s disease, including genetic markers and genomic structural variations with this feed.