Please use this identifier to cite or link to this item: http://hdl.handle.net/20.500.11889/8022
Title: Distinct dynamics and interaction patterns in H- and K-Ras oncogenic P-loop mutants
Authors: Sayyed-Ahmad, Abdallah 
Prakash, Priyanka 
Gorfe, Alemayehu A. 
Keywords: Ras proteins;Cancer - Chemotherapy;DNA - Transformations;Oncogenic mutations;Conformational transitions;Molecular dynamics
Issue Date: 2017
Abstract: Despiteyearsofstudy,thestructuralordynamicalbasisforthedifferentialreactivityandoncogenicityofRasisoformsand mutantsremainsunclear.Inthisstudy,weinvestigatedtheeffectsofaminoacidvariationsonthestructureanddynamics ofwildtypeandoncogenicmutantsG12D,G12V,andG13DofH-andK-Rasproteins.Basedondatafromms-scalemoleculardynamicssimulations,weshowthattheoverallstructureoftheproteinsremainssimilarbutthereareimportantdifferencesindynamicsandinteractionnetworks.Weidentifieddifferencesinresidueinteractionpatternsaroundthecanonical switchanddistalloopregions,andpersistentsodiumionbindingneartheGTPparticularlyintheG13Dmutants.Our resultsalsosuggestthatdifferentRasvariantshavedistinctlocalstructuralfeaturesandinteractionswiththeGTP,variationsthathavethepotentialtoaffectGTPreleaseandhydrolysis.Furthermore,wefoundthatH-RasproteinsandparticularlytheG12VandG13DvariantsaresignificantlymoreflexiblethantheirK-Rascounterparts.Finally,whilemostofthe simulatedproteinssampledtheeffector-interactingstate2conformationalstate,G12VandG13DH-Rasadoptedanopen switchstate1conformationthatisdefectiveineffectorinteraction.ThesedifferenceshaveimplicationsforRasGTPase activity,effectororexchangefactorbinding,dimerizationandmembraneinteraction.
URI: http://hdl.handle.net/20.500.11889/8022
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