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BBA - Proteins and Proteomics (v.1834, #5)

Editorial Board (pp. i).

The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly by Ugo Bastolla; Markus Porto; H. Eduardo Roman (pp. 817-819).

A broad view of scaffolding suggests that scaffolding proteins can actively control regulation and signaling of multienzyme complexes through allostery by Ruth Nussinov; Buyong Ma; Chung-Jung Tsai (pp. 820-829).

Enzymes often work sequentially in pathways; and consecutive reaction steps are typically carried out by molecules associated in the same multienzyme complex. Localization confines the enzymes; anchors them; increases the effective concentration of substrates and products; and shortens pathway timescales; however, it does not explain enzyme coordination or pathway branching. Here, we distinguish between metabolic and signaling multienzyme complexes. We argue for a central role of scaffolding proteins in regulating multienzyme complexes signaling and suggest that metabolic multienzyme complexes are less dependent on scaffolding because they undergo conformational control through direct subunit–subunit contacts. In particular, we propose that scaffolding proteins have an essential function in controlling branching in signaling pathways. This new broadened definition of scaffolding proteins goes beyond cases such as the classic yeast mitogen-activated protein kinase Ste5 and encompasses proteins such as E3 ligases which lack active sites and work via allostery. With this definition, we classify the mechanisms of multienzyme complexes based on whether the substrates are transferred through the involvement of scaffolding proteins, and outline the functional merits to metabolic or signaling pathways. Overall, while co-localization topography helps multistep pathways non-specifically, allosteric regulation requires precise multienzyme organization and interactions and works via population shift, either through direct enzyme subunit–subunit interactions or through active involvement of scaffolding proteins. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.► We classify multienzyme complexes based on the presence of scaffolding proteins. ► Scaffolding proteins typically allosterically regulate signaling multienzyme complexes. ► Scaffolding proteins are rare in metabolic multienzyme complexes. ► Allostery plays a key role in the presence and absence of scaffolding proteins. ► Scaffolding proteins can control pathway branching in multienzyme complexes.

Keywords: Multi-enzyme complex; Allosteric; Multiprotein; Multi-protein; Population shift; Conformational selection

Thermodynamics of allostery paves a way to allosteric drugs by Igor N. Berezovsky (pp. 830-835).

We overview here our recent work on the thermodynamic view of allosteric regulation and communication. Starting from the geometry-based prediction of regulatory binding sites in a static structure, we move on to exploring a connection between ligand binding and the intrinsic dynamics of the protein molecule. We describe here two recently introduced measures, binding leverage and leverage coupling, which allow one to analyze the molecular basis of allosteric regulation. We discuss the advantages of these measures and show that they work universally in proteins of different sizes, oligomeric states, and functions. We also point the problems that have to be solved before completing an atomic level description of allostery, and briefly discuss ideas for computational design of allosteric drugs. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.► Recent works on thermodynamic view of allostery are discussed. ► Local closeness is a static, geometry-based predictor of binding sites. ► Binding leverage: ligand binding affects conformational changes. ► Leverage coupling allows to quantify allosteric communication. ► Ideas for design of allosteric drugs are discussed.

Keywords: Allostery; Local closeness; Binding leverage; Leverage coupling; Allosteric drug

Characterizing conformation changes in proteins through the torsional elastic response by Helena G. Dos Santos; Javier Klett; Mendez Raúl Méndez; Ugo Bastolla (pp. 836-846).

The relationship between functional conformation changes and thermal dynamics of proteins is investigated with the help of the torsional network model (TNM), an elastic network model in torsion angle space that we recently introduced. We propose and test a null-model of “random” conformation changes that assumes that the contributions of normal modes to conformation changes are proportional to their contributions to thermal fluctuations. Deviations from this null model are generally small. When they are large and significant, they consist in conformation changes that are represented by very few low frequency normal modes and overcome small energy barriers. We interpret these features as the result of natural selection favoring the intrinsic protein dynamics consistent with functional conformation changes. These “selected” conformation changes are more frequently associated to ligand binding, and in particular phosphorylation, than to pairs of conformations with the same ligands. This deep relationship between the thermal dynamics of a protein, represented by its normal modes, and its functional dynamics can reconcile in a unique framework the two models of conformation changes, conformational selection and induced fit. The program TNM that computes torsional normal modes and analyzes conformation changes is available upon request. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.► Elastic network of torsion angles representing all protein atoms ► Null-model of “random” conformation changes based on linear response theory ► Significant deviations suggest functional motions with small energy barriers. ► They occur more frequently for phosphorylation, dimeric proteins, ligand binding. ► Reconcile in a unique framework conformational selection and induced fit.

Keywords: Normal mode analysis; Elastic network model; Torsion angle; Conformation change; Allostery; Energy barrier

Advanced replica-exchange sampling to study the flexibility and plasticity of peptides and proteins by Katja Ostermeir; Martin Zacharias (pp. 847-853).

Molecular dynamics (MD) simulations are ideally suited to investigate protein and peptide plasticity and flexibility simultaneously at high spatial (atomic) and high time resolution. However, the applicability is still limited by the force field accuracy and by the maximum simulation time that can be routinely achieved in current MD simulations. In order to improve the sampling the replica-exchange (REMD) methodology has become popular and is now the most widely applied advanced sampling approach. Many variants of the REMD method have been designed to reduce the computational demand or to enhance sampling along specific sets of conformational variables. An overview on recent methodological advances and discussion of specific aims and advantages of the approaches will be given. Applications in the area of free energy simulations and advanced sampling of intrinsically disordered peptides and proteins will also be discussed. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.► Replica exchange sampling is increasingly important to study protein plasticity. ► Discussion of strengths and weaknesses of the available methods. ► Recent developments of Hamiltonian-replica-exchange approaches are covered. ► REMD techniques are also beneficial to study disordered protein segments.

Keywords: Molecular dynamics simulation; Peptide and protein folding; Potential scaling; Conformational sampling; Accelerated sampling; Force field calculation

Stability and rigidity/flexibility—Two sides of the same coin? by Tatyana B. Mamonova; Anna V. Glyakina; Oxana V. Galzitskaya; Maria G. Kurnikova (pp. 854-866).

Protein molecules require both flexibility and rigidity for functioning. The fast and accurate prediction of protein rigidity/flexibility is one of the important problems in protein science. We have determined flexible regions for four homologous pairs from thermophilic and mesophilic organisms by two methods: the fast FoldUnfold which uses amino acid sequence and the time consuming MDFirst which uses three-dimensional structures. We demonstrate that both methods allow determining flexible regions in protein structure. For three of the four thermophile–mesophile pairs of proteins, FoldUnfold predicts practically the same flexible regions which have been found by the MD/First method. As expected, molecular dynamics simulations show that thermophilic proteins are more rigid in comparison to their mesophilic homologues. Analysis of rigid clusters and their decomposition provides new insights into protein stability. It has been found that the local networks of salt bridges and hydrogen bonds in thermophiles render their structure more stable with respect to fluctuations of individual contacts. Such network includes salt bridge triads Agr-Glu-Lys and Arg-Glu-Arg, or salt bridges (such as Arg-Glu) connected with hydrogen bonds. This ionic network connects alpha helices and rigidifies the structure. Mesophiles can be characterized by stand alone salt bridges and hydrogen bonds or small ionic clusters. Such difference in the network of salt bridges results in different flexibility of homologous proteins. Combining both approaches allows characterizing structural features in atomic detail that determine the rigidity/flexibility of a protein structure. This article is a part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.► Knowledge based FoldUnfold predicts the same flexible regions as found by MDFirst. ► MDFirst uses atom contact fluctuations from MD to build graphs of protein structure. ► Rigid cluster hierarchies are different in thermophiles and mesophiles. ► In MD simulations thermophiles are less flexible then their mesophilic homologs. ► Salt bridges in protein core contribute to stability and rigidity of thermophiles.

Keywords: Molecular dynamics simulation; Proteins from thermophilic and mesophilic organisms; Flexible region; Hydrogen bond; Salt bridge

How conformational changes can affect catalysis, inhibition and drug resistance of enzymes with induced-fit binding mechanism such as the HIV-1 protease by Thomas R. Weikl; Bahram Hemmateenejad (pp. 867-873).

A central question is how the conformational changes of proteins affect their function and the inhibition of this function by drug molecules. Many enzymes change from an open to a closed conformation upon binding of substrate or inhibitor molecules. These conformational changes have been suggested to follow an induced-fit mechanism in which the molecules first bind in the open conformation in those cases where binding in the closed conformation appears to be sterically obstructed such as for the HIV-1 protease. In this article, we present a general model for the catalysis and inhibition of enzymes with induced-fit binding mechanism. We derive general expressions that specify how the overall catalytic rate of the enzymes depends on the rates for binding, for the conformational changes, and for the chemical reaction. Based on these expressions, we analyze the effect of mutations that mainly shift the conformational equilibrium on catalysis and inhibition. If the overall catalytic rate is limited by product unbinding, we find that mutations that destabilize the closed conformation relative to the open conformation increase the catalytic rate in the presence of inhibitors by a factor exp( ΔΔG_C/ RT) where ΔΔG_C is the mutation-induced shift of the free-energy difference between the conformations. This increase in the catalytic rate due to changes in the conformational equilibrium is independent of the inhibitor molecule and, thus, may help to understand how non-active-site mutations can contribute to the multi-drug-resistance that has been observed for the HIV-1 protease. A comparison to experimental data for the non-active-site mutation L90M of the HIV-1 protease indicates that the mutation slightly destabilizes the closed conformation of the enzyme. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.Display Omitted► We present a general model for enzymes with induced-fit binding mechanism. ► The enzymes change from an open to a closed conformation during binding. ► Non-active-site mutations affect catalysis and inhibition in the model. ► Mutations destabilizing the closed conformation contribute to multi-drug resistance. ► The mutation L90M of the HIV-1 protease slightly destabilizes the closed conformation.

Keywords: Enzyme dynamics; Induced fit; Conformational selection; HIV-1 protease; Non-active-site mutation; Multi-drug resistance

Functional site plasticity in domain superfamilies by Benoit H. Dessailly; Natalie L. Dawson; Kenji Mizuguchi; Christine A. Orengo (pp. 874-889).

We present, to our knowledge, the first quantitative analysis of functional site diversity in homologous domain superfamilies. Different types of functional sites are considered separately. Our results show that most diverse superfamilies are very plastic in terms of the spatial location of their functional sites. This is especially true for protein–protein interfaces. In contrast, we confirm that catalytic sites typically occupy only a very small number of topological locations. Small-ligand binding sites are more diverse than expected, although in a more limited manner than protein–protein interfaces. In spite of the observed diversity, our results also confirm the previously reported preferential location of functional sites. We identify a subset of homologous domain superfamilies where diversity is particularly extreme, and discuss possible reasons for such plasticity, i.e. structural diversity. Our results do not contradict previous reports of preferential co-location of sites among homologues, but rather point at the importance of not ignoring other sites, especially in large and diverse superfamilies. Data on sites exploited by different relatives, within each well annotated domain superfamily, has been made accessible from the CATH website in order to highlight versatile superfamilies or superfamilies with highly preferential sites. This information is valuable for system biology and knowledge of any constraints on protein interactions could help in understanding the dynamic control of networks in which these proteins participate. The novelty of our work lies in the comprehensive nature of the analysis – we have used a significantly larger dataset than previous studies – and the fact that in many superfamilies we show that different parts of the domain surface are exploited by different relatives for ligand/protein interactions, particularly in superfamilies which are diverse in sequence and structure, an observation not previously reported on such a large scale. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.•Most diverse domain superfamilies have very diverse functional site locations.•Catalytic sites are found in a small, restricted number of topological positions.•Location of small-ligand binding sites is more diverse than expected.•Protein–protein interfaces display the most flexibility in functional site locations.

Keywords: Protein domain structure; Functional diversity; Structural diversity; Functional residues; Functional site diversity

Long indels are disordered: A study of disorder and indels in homologous eukaryotic proteins by Sara Light; Rauan Sagit; Diana Ekman; Arne Elofsson (pp. 890-897).

Proteins evolve through point mutations as well as by insertions and deletions (indels). During the last decade it has become apparent that protein regions that do not fold into three-dimensional structures, i.e. intrinsically disordered regions, are quite common. Here, we have studied the relationship between protein disorder and indels using HMM–HMM pairwise alignments in two sets of orthologous eukaryotic protein pairs. First, we show that disordered residues are much more frequent among indel residues than among aligned residues and, also are more prevalent among indels than in coils. Second, we observed that disordered residues are particularly common in longer indels. Disordered indels of short-to-medium size are prevalent in the non-terminal regions of proteins while the longest indels, ordered and disordered alike, occur toward the termini of the proteins where new structural units are comparatively well tolerated. Finally, while disordered regions often evolve faster than ordered regions and disorder is common in indels, there are some previously recognized protein families where the disordered region is more conserved than the ordered region. We find that these rare proteins are often involved in information processes, such as RNA processing and translation. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.► Disordered residues are more frequent among indels than among aligned residues. ► Disordered residues are particularly common in longer indels. ► Ordered non-terminal indels are short. ► The longest indels, ordered and disordered, occur toward the termini of the proteins.

Keywords: Intrinsically disordered protein; Indel; Protein evolution protein structure; Sequence alignment

Quantification and functional analysis of modular protein evolution in a dense phylogenetic tree by Andrew D. Moore; Sonja Grath; Schuler Andreas Schüler; Ann K. Huylmans; Erich Bornberg-Bauer (pp. 898-907).

Modularity is a hallmark of molecular evolution. Whether considering gene regulation, the components of metabolic pathways or signaling cascades, the ability to reuse autonomous modules in different molecular contexts can expedite evolutionary innovation. Similarly, protein domains are the modules of proteins, and modular domain rearrangements can create diversity with seemingly few operations in turn allowing for swift changes to an organism's functional repertoire. Here, we assess the patterns and functional effects of modular rearrangements at high resolution. Using a well resolved and diverse group of pancrustaceans, we illustrate arrangement diversity within closely related organisms, estimate arrangement turnover frequency and establish, for the first time, branch-specific rate estimates for fusion, fission, domain addition and terminal loss. Our results show that roughly 16 new arrangements arise per million years and that between 64% and 81% of these can be explained by simple, single-step modular rearrangement events. We find evidence that the frequencies of fission and terminal deletion events increase over time, and that modular rearrangements impact all levels of the cellular signaling apparatus and thus may have strong adaptive potential. Novel arrangements that cannot be explained by simple modular rearrangements contain a significant amount of repeat domains that occur in complex patterns which we term “supra-repeats”. Furthermore, these arrangements are significantly longer than those with a single-step rearrangement solution, suggesting that such arrangements may result from multi-step events. In summary, our analysis provides an integrated view and initial quantification of the patterns and functional impact of modular protein evolution in a well resolved phylogenetic tree. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.► Modular evolution can create large diversity over evolutionarily small time-scales. ► We derive rates of arrangement gain/loss and quantify key events in modular evolution. ► The majority of novel arrangements can be formed by one of four mechanisms. ► A small number of novel arrangements harbor unusual patterns of “supra-repeats”. ► We explore possible functions preferentially associated with modular rearrangements.

Keywords: Abbreviations; MDA; multi-domain arrangement; SDA; single-domain arrangement; ORA; over-representation analysis; My; million yearsModular protein evolution; Protein domain; Drosophila genome evolution; Pfam; Bioinformatics

Optimization of reorganization energy drives evolution of the designed Kemp eliminase KE07 by A. Labas; E. Szabo; L. Mones; M. Fuxreiter (pp. 908-917).

Understanding enzymatic evolution is essential to engineer enzymes with improved activities or to generate enzymes with tailor-made activities. The computationally designed Kemp eliminase KE07 carries out an unnatural reaction by converting of 5-nitrobenzisoxazole to cyanophenol, but its catalytic efficiency is significantly lower than those of natural enzymes. Three series of designed Kemp eliminases (KE07, KE70, KE59) were shown to be evolvable with considerable improvement in catalytic efficiency. Here we use the KE07 enzyme as a model system to reveal those forces, which govern enzymatic evolution and elucidate the key factors for improving activity. We applied the Empirical Valence Bond (EVB) method to construct the free energy pathway of the reaction in the original KE07 design and the evolved R7 1/3H variant. We analyzed catalytic effect of residues and demonstrated that not all mutations in evolution are favorable for activity. In contrast to the small decrease in the activation barrier, in vitro evolution significantly reduced the reorganization energy. We developed an algorithm to evaluate group contributions to the reorganization energy and used this approach to screen for KE07 variants with potential for improvement. We aimed to identify those mutations that facilitate enzymatic evolution, but might not directly increase catalytic efficiency. Computational results in accord with experimental data show that all mutations, which appear during in vitro evolution were either neutral or favorable for the reorganization energy. These results underscore that distant mutations can also play role in optimizing efficiency via their contribution to the reorganization energy. Exploiting this principle could be a promising strategy for computer-aided enzyme design. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.

Keywords: Abbreviations; MD; molecular dynamics; EVB; Empirical Valence Bond; SCAAS; surface constraint all atom solvent; TS; transition state; RS; reactant state; PS; product state; LRF; local reaction field; PDLD/S; semi-microscopic Protein Dipoles Langevin Dipoles; LRA; linear response approximationEnzymatic evolution; Kemp eliminase; Computational enzyme design; Reorganization energy; Enzymatic catalysis; Computer simulation

Protein disorder, prion propensities, and self-organizing macromolecular collectives by Liliana Malinovska; Sonja Kroschwald; Simon Alberti (pp. 918-931).

Eukaryotic cells are partitioned into functionally distinct self-organizing compartments. But while the biogenesis of membrane-surrounded compartments is beginning to be understood, the organizing principles behind large membrane-less structures, such as RNA-containing granules, remain a mystery. Here, we argue that protein disorder is an essential ingredient for the formation of such macromolecular collectives. Intrinsically disordered regions (IDRs) do not fold into a well-defined structure but rather sample a range of conformational states, depending on the local conditions. In addition to being structurally versatile, IDRs promote multivalent and transient interactions. This unique combination of features turns intrinsically disordered proteins into ideal agents to orchestrate the formation of large macromolecular assemblies. The presence of conformationally flexible regions, however, comes at a cost, for many intrinsically disordered proteins are aggregation-prone and cause protein misfolding diseases. This association with disease is particularly strong for IDRs with prion-like amino acid composition. Here, we examine how disease-causing and normal conformations are linked, and discuss the possibility that the dynamic order of the cytoplasm emerges, at least in part, from the collective properties of intrinsically disordered prion-like domains. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.► Many prion-like sequences are intrinsically disordered protein interaction domains. ► They promote phase transitions and the formation of large macromolecular assemblies. ► Prion-like domains may be essential for the spatiotemporal organization of the cell. ► The structural flexibility also makes them prone to misfold and aggregate. ► As a consequence, they are emerging as causes of protein misfolding diseases.

Keywords: Abbreviations; IDP; intrinsically disordered protein; IDR; intrinsically disordered region; PrD; prion domain; IPOD; insoluble protein deposit; JUNQ; juxtanuclear protein quality control; RNP; ribonucleoproteinProtein disorder; Self-organization; Phase transition; Prion; Amyloid

Unusual biophysics of intrinsically disordered proteins by Vladimir N. Uversky (pp. 932-951).

Research of a past decade and a half leaves no doubt that complete understanding of protein functionality requires close consideration of the fact that many functional proteins do not have well-folded structures. These intrinsically disordered proteins (IDPs) and proteins with intrinsically disordered protein regions (IDPRs) are highly abundant in nature and play a number of crucial roles in a living cell. Their functions, which are typically associated with a wide range of intermolecular interactions where IDPs possess remarkable binding promiscuity, complement functional repertoire of ordered proteins. All this requires a close attention to the peculiarities of biophysics of these proteins. In this review, some key biophysical features of IDPs are covered. In addition to the peculiar sequence characteristics of IDPs these biophysical features include sequential, structural, and spatiotemporal heterogeneity of IDPs; their rough and relatively flat energy landscapes; their ability to undergo both induced folding and induced unfolding; the ability to interact specifically with structurally unrelated partners; the ability to gain different structures at binding to different partners; and the ability to keep essential amount of disorder even in the bound form. IDPs are also characterized by the “turned-out” response to the changes in their environment, where they gain some structure under conditions resulting in denaturation or even unfolding of ordered proteins. It is proposed that the heterogeneous spatiotemporal structure of IDPs/IDPRs can be described as a set of foldons, inducible foldons, semi-foldons, non-foldons, and unfoldons. They may lose their function when folded, and activation of some IDPs is associated with the awaking of the dormant disorder. It is possible that IDPs represent the “edge of chaos” systems which operate in a region between order and complete randomness or chaos, where the complexity is maximal. This article is part of a Special Issue entitled: The emerging dynamic view of proteins: Protein plasticity in allostery, evolution and self-assembly.► Intrinsically disordered proteins (IDPs) are important members of the protein kingdom. ► They possess remarkable sequential, structural, spatiotemporal, and functional heterogeneity. ► They have rough and relatively flat energy landscapes. ► They might contain foldons, inducible foldons, semi-foldons and non-foldons. ► IDPs can be considered as the “edge of chaos” systems.

Keywords: Intrinsically disordered protein; Structural heterogeneity; Complex systems; Protein function

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BBA - Proteins and Proteomics (v.1834, #5)