Entropic Stabilization of Proteins and Its Proteomic Consequences 英文参考文献.docVIP

EntropicStabilizationofProteins andItsProteomicConsequences Igor N.Berezovsky1,William W. Chen1,2,Paul J.Choi1,Eugene I.Shakhnovich1* 1DepartmentofChemistryandChemicalBiology,HarvardUniversity,Cambridge,Massachusetts,UnitedStatesofAmerica,2DepartmentofBiophysics,HarvardUniversity, Cambridge,Massachusetts,UnitedStatesofAmerica Evolutionary traces of thermophilic adaptation are manifest, on the whole-genome level, in compositional biases toward certain types of amino acids. However, it is sometimes difficult to discern their causes without a clear understandingofunderlyingphysicalmechanismsofthermalstabilizationofproteins.Forexample,itiswell-known that hyperthermophiles feature a greater proportion of charged residues, but, surprisingly, the excess of positively chargedresiduesisalmostentirelyduetolysinesbutnotargininesinthemajorityofhyperthermophilicgenomes.All- atom simulations show that lysines have a much greater number of accessible rotamers than arginines of similar degree of burial in folded states of proteins. This finding suggests that lysines would preferentially entropically stabilize the native state. Indeed, we show in computational experiments that arginine-to-lysine amino acid substitutions result in noticeable stabilization of proteins. We then hypothesize that if evolution uses this physical mechanism as a complement to electrostatic stabilization in its strategies of thermophilic adaptation, then hyperthermostableorganismswouldhavemuchgreatercontentoflysinesintheirproteomesthancomparablysized andsimilarlychargedarginines.Consistentwiththat,high-throughputcomparativeanalysisofcompleteproteomes showsextremelystrongbiastowardarginine-to-lysinereplacementinhyperthermophilicorganismsandoverallmuch greater content of lysines than arginines in hyperthermophiles. This finding cannot be explained by genomic GC compositionalbiasesorbytheuniversaltrendofaminoacidgainandlossinproteinevolution.Wediscoveredherea novelentropicmechanismofproteinthermostability