Browsing by Author "Fuxreiter, Monika"

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    Frustration in Fuzzy Protein Complexes Leads to Interaction Versatility
    (American Chemical Society, 2021) Freiberger, Maria I.; Wolynes, Peter G.; Ferreiro, Diego U.; Fuxreiter, Monika; Center for Theoretical Biological Physics
    Disordered proteins frequently serve as interaction hubs involving a constrained variety of partners. Complexes with different partners frequently exhibit distinct binding modes, involving regions that remain disordered in the bound state. While the conformational properties of disordered proteins are well-characterized in their free states, less is known about the molecular mechanisms by which specificity can be achieved not with one but with multiple partners. Using the energy landscape theory concept of protein frustration, we demonstrate that complexes of disordered proteins exhibit a high degree of local frustration, especically at the binding interface. These suboptimal interactions lead to the possibility of multiple bound substates, each displaying distinct frustration patterns, which are differently populated in complexes with different partners. These results explain how specificity of disordered proteins can be achieved without a single common bound conformation and how the confliict between different interactions can be used to control the binding to multiple partners.
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    Fuzziness and Frustration in the Energy Landscape of Protein Folding, Function, and Assembly
    (American Chemical Society, 2021) Gianni, Stefano; Freiberger, María Inés; Jemth, Per; Ferreiro, Diego U.; Wolynes, Peter G.; Fuxreiter, Monika; Center for Theoretical Biological Physics
    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.