Significance of Knotted Structures for Function of Proteins and Nucleic Acids - September 17-21, 2014

Significance of Knotted Structures for Function of Proteins and Nucleic Acids

Poster Session II

30 – POS Board 2 A Relationship between Coevolutionary Information, Folding Landscapes and the Thermodynamics of Natural Sequence Selection Faruck Morcos , Nicholas P. Schafer, Ryan R. Cheng, Jose N. Onuchic, Peter G. Wolynes. Rice University, Houston, USA. As a consequence of evolutionary sequence optimization, natural proteins are energetically more stable in their native state than in the molten globule states, resulting in an energy stabilization gap. Although the mechanisms behind evolutionary optimization are far from being resolved, it is possible to quantify the extent at which sequences have been optimized by such evolutionary mechanisms in a framework consistent with current theories of protein folding and experimental observations. Methods : We compare the landscape statistics for a transferable energy function that is successful in structure prediction known as Associative memory, Water mediated, Structure and Energy Model (AWSEM) with direct residue-residue couplings obtained using Direct Coupling Analysis (DCA) and inferred from sequence alignments of protein families to estimate the effective temperature at which natural, foldable protein sequences have been selected in sequence space, T sel . This temperature quantifies the importance of folding energetics to molecular evolution. Results : We considered eight different families, with abundant number of sequences (> 4500), known experimental structures, lengths from 60 to 286aa and distinct folds. For each family, we estimated the selection temperature T sel and the glass transition temperature T g for the native sequences using experimentally determined folding temperatures T f and the relationship between AWSEM and DCA Hamiltonians. We then computed T f /T g ratios, which are a metric of evolutionary folding optimization. Conclusions : The resulting estimates of T f /T g are consistent with previous estimates based on setting up correspondences with lattice models and through comparisons with laboratory folding kinetics. Consistent estimates for T sel and T f /T g are also obtained using an alternate scheme, which relies on the comparison of residue coevolution with experimental stability changes upon single site mutations. Our results provide new evidence for funneling and suggest new directions for protein modeling and design.

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