Abstract
ConspectusAre 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.
Highlights
The crystallographers’ paradigm that function follows structure has played a pivotal role in protein science
The molecular movements and rearrangements needed for function range from ps side-chain rotations to subunit and domain rearrangements on the ms time scale and on to the most extreme examples of protein dynamics: unfolding and/or folding of an entire protein, which can take times varying from microseconds to several seconds or minutes.[6]
It has been shown that partner interactions reduce but do not always entirely eliminate local frustration in the final complexes of disordered protein regions. These results indicate that binding-induced folding often results in suboptimal interactions both at the binding interface as well as in the structured part of the protein
Summary
The crystallographers’ paradigm that function follows structure has played a pivotal role in protein science. Based on the local sequence biases with different possible binding sites, the pool of possible binding modes leading to fuzziness can be quantified.[53] Frustration in the binding landscape may stem from non-native interactions as observed for c-Myb/KIX61−63 or ACTR/ NCBD.[64,65] All these alternative binding modes expand the functional repertoire of proteins, as the relative populations of the different conformational substates can be shifted according to the cellular milieu.[66]. While many solved complexes between disordered regions and folded domains are structurally well-defined, like that for CID/ NCBD, there are examples of positive selection for interactions with fuzzy complexes.[68,69] Coevolutionary analysis provides a powerful method to identify intermolecular interaction partners as well as long-range intramolecular contacts within a protein. It is clear that selection has generated a wide spectrum of local frustration levels in natural protein−protein interactions, resulting in well-defined complexes as well as sometimes structurally heterogeneous complexes
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