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Evidence for the principle of minimal frustration in the evolution of protein folding landscapes.

ABSTRACT: Theoretical and experimental studies have firmly established that protein folding can be described by a funneled energy landscape. This funneled energy landscape is the result of foldable protein sequences evolving following the principle of minimal frustration, which allows proteins to rapidly fold to their native biologically functional conformations. For a protein family with a given functional fold, the principle of minimal frustration suggests that, independent of sequence, all proteins within this family should fold with similar rates. However, depending on the optimal living temperature of the organism, proteins also need to modulate their thermodynamic stability. Consequently, the difference in thermodynamic stability should be primarily caused by differences in the unfolding rates. To test this hypothesis experimentally, we performed comprehensive thermodynamic and kinetic analyses of 15 different proteins from the thioredoxin family. Eight of these thioredoxins were extant proteins from psychrophilic, mesophilic, or thermophilic organisms. The other seven protein sequences were obtained using ancestral sequence reconstruction and can be dated back over 4 billion years. We found that all studied proteins fold with very similar rates but unfold with rates that differ up to three orders of magnitude. The unfolding rates correlate well with the thermodynamic stability of the proteins. Moreover, proteins that unfold slower are more resistant to proteolysis. These results provide direct experimental support to the principle of minimal frustration hypothesis.

SUBMITTER: Tzul FO

PROVIDER: S-EPMC5338549 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Evidence for the principle of minimal frustration in the evolution of protein folding landscapes.

Tzul Franco O FO Vasilchuk Daniel D Makhatadze George I GI

Proceedings of the National Academy of Sciences of the United States of America 20170214 9

Theoretical and experimental studies have firmly established that protein folding can be described by a funneled energy landscape. This funneled energy landscape is the result of foldable protein sequences evolving following the principle of minimal frustration, which allows proteins to rapidly fold to their native biologically functional conformations. For a protein family with a given functional fold, the principle of minimal frustration suggests that, independent of sequence, all proteins wit ...[more]

PMID: 28196883

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Project description:Are all protein interactions fully optimized? Do suboptimal interactions compromise specificity? What is the functional impact of frustration? Why does evolution not optimize some contacts? Proteins and their complexes are best described as ensembles of states populating an energy landscape. These ensembles vary in breadth from narrow ensembles clustered around a single average X-ray structure to broader ensembles encompassing a few different functional "taxonomic" states on to near continua of rapidly interconverting conformations, which are called "fuzzy" or even "intrinsically disordered". Here we aim to provide a comprehensive framework for confronting the structural and dynamical continuum of protein assemblies by combining the concepts of energetic frustration and interaction fuzziness. The diversity of the protein structural ensemble arises from the frustrated conflicts between the interactions that create the energy landscape. When frustration is minimal after folding, it results in a narrow ensemble, but residual frustrated interactions result in fuzzy ensembles, and this fuzziness allows a versatile repertoire of biological interactions. Here we discuss how fuzziness and frustration play off each other as proteins fold and assemble, viewing their significance from energetic, functional, and evolutionary perspectives.We demonstrate, in particular, that the common physical origin of both concepts is related to the ruggedness of the energy landscapes, intramolecular in the case of frustration and intermolecular in the case of fuzziness. Within this framework, we show that alternative sets of suboptimal contacts may encode specificity without achieving a single structural optimum. Thus, we demonstrate that structured complexes may not be optimized, and energetic frustration is realized via different sets of contacts leading to multiplicity of specific complexes. Furthermore, we propose that these suboptimal, frustrated, or fuzzy interactions are under evolutionary selection and expand the biological repertoire by providing a multiplicity of biological activities. In accord, we show that non-native interactions in folding or interaction landscapes can cooperate to generate diverse functional states, which are essential to facilitate adaptation to different cellular conditions. Thus, we propose that not fully optimized structures may actually be beneficial for biological activities of proteins via an alternative set of suboptimal interactions. The importance of such variability has not been recognized across different areas of biology.This account provides a modern view on folding, function, and assembly across the protein universe. The physical framework presented here is applicable to the structure and dynamics continuum of proteins and opens up new perspectives for drug design involving not fully structured, highly dynamic protein assemblies.

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Evidence for the principle of minimal frustration in the evolution of protein folding landscapes.

Publications

Evidence for the principle of minimal frustration in the evolution of protein folding landscapes.

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