scholarly journals Conformational dynamics and enzyme evolution

2018 ◽  
Vol 15 (144) ◽  
pp. 20180330 ◽  
Author(s):  
Dušan Petrović ◽  
Valeria A. Risso ◽  
Shina Caroline Lynn Kamerlin ◽  
Jose M. Sanchez-Ruiz
Keyword(s):  
Biological Function ◽  
Dynamic Properties ◽  
Conformational Dynamics ◽  
Enzyme Evolution ◽  
Single Mutation ◽  
Evolutionary Changes ◽  
Conformational Diversity ◽  
Evolutionary Trajectories ◽  
Experimental Approaches ◽  
Environmental Temperatures

Enzymes are dynamic entities, and their dynamic properties are clearly linked to their biological function. It follows that dynamics ought to play an essential role in enzyme evolution. Indeed, a link between conformational diversity and the emergence of new enzyme functionalities has been recognized for many years. However, it is only recently that state-of-the-art computational and experimental approaches are revealing the crucial molecular details of this link. Specifically, evolutionary trajectories leading to functional optimization for a given host environment or to the emergence of a new function typically involve enriching catalytically competent conformations and/or the freezing out of non-competent conformations of an enzyme. In some cases, these evolutionary changes are achieved through distant mutations that shift the protein ensemble towards productive conformations. Multifunctional intermediates in evolutionary trajectories are probably multi-conformational, i.e. able to switch between different overall conformations, each competent for a given function. Conformational diversity can assist the emergence of a completely new active site through a single mutation by facilitating transition-state binding. We propose that this mechanism may have played a role in the emergence of enzymes at the primordial, progenote stage, where it was plausibly promoted by high environmental temperatures and the possibility of additional phenotypic mutations.

scholarly journals Behavioral syndromes shape evolutionary trajectories via conserved genetic architecture

2019 ◽  
Author(s):  
Raphael Royauté ◽  
Ann Hedrick ◽  
Ned A. Dochtermann
Keyword(s):  
Genetic Architecture ◽  
Behavioral Syndromes ◽  
Behavioral Syndrome ◽  
Cellular Mechanisms ◽  
Genetic Covariance ◽  
Behavioral Traits ◽  
Field Crickets ◽  
Evolutionary Changes ◽  
Evolutionary Trajectories ◽  
Gryllus Integer

AbstractBehaviors are often correlated within broader syndromes, creating the potential for evolution in one behavior to drive evolutionary changes in other behaviors. Despite demonstrations that behavioral syndromes are common across taxa, whether this potential for evolutionary effects is realized has not yet been demonstrated. Here we show that populations of field crickets (Gryllus integer) exhibit a genetically conserved behavioral syndrome structure despite differences in average behaviors. We found that the distribution of genetic variation and genetic covariance among behavioral traits was consistent with genes and cellular mechanisms underpinning behavioral syndromes rather than correlated selection. Moreover, divergence among populations’ average behaviors was constrained by the genetically conserved behavioral syndrome. Our results demonstrate that a conserved genetic architecture linking behaviors has shaped the evolutionary trajectories of populations in disparate environments—illustrating an important way by which behavioral syndromes result in shared evolutionary fates.

scholarly journals DNA sequence is a major determinant of tetrasome dynamics

2019 ◽  
Author(s):  
O. Ordu ◽  
A. Lusser ◽  
N. H. Dekker
Keyword(s):  
Dna Sequence ◽  
Dna Sequences ◽  
Dynamic Properties ◽  
Conformational Dynamics ◽  
Magnetic Tweezers ◽  
Torsional Stress ◽  
High Affinity ◽  
Canonical State ◽  
Left And Right ◽  
Dna Wrapping

ABSTRACTEukaryotic genomes are hierarchically organized into protein-DNA assemblies for compaction into the nucleus. Nucleosomes, with the (H3-H4)2 tetrasome as a likely intermediate, are highly dynamic in nature by way of several different mechanisms. We have recently shown that tetrasomes spontaneously change the direction of their DNA wrapping between left- and right-handed conformations, which may prevent torque build-up in chromatin during active transcription or replication. DNA sequence has been shown to strongly affect nucleosome positioning throughout chromatin. It is not known, however, whether DNA sequence also impacts the dynamic properties of tetrasomes. To address this question, we examined tetrasomes assembled on a high-affinity DNA sequence using freely orbiting magnetic tweezers. In this context, we also studied the effects of mono- and divalent salts on the flipping dynamics. We found that neither DNA sequence nor altered buffer conditions affect overall tetrasome structure. In contrast, tetrasomes bound to high-affinity DNA sequences showed significantly altered flipping kinetics, predominantly via a reduction in the lifetime of the canonical state of left-handed wrapping. Increased mono- and divalent salt concentrations counteracted this behaviour. Thus, our study indicates that high-affinity DNA sequences impact not only the positioning of the nucleosome, but that they also endow the subnucleosomal tetrasome with enhanced conformational plasticity. This may provide a means to prevent histone loss upon exposure to torsional stress, thereby contributing to the integrity of chromatin at high-affinity sites.STATEMENT OF SIGNIFICANCECanonical (H3-H4)2 tetrasomes possess high conformational flexibility, as evidenced by their spontaneous flipping between states of left- and right-handed DNA wrapping. Here, we show that these conformational dynamics of tetrasomes cannot be described by a fixed set of rates over all conditions. Instead, an accurate description of their behavior must take into account details of their loading, in particular the underlying DNA sequence. In vivo, differences in tetrasome flexibility could be regulated by modifications of the histone core or the tetrasomal DNA, and as such constitute an intriguing, potentially adjustable mechanism for chromatin to accommodate the torsional stress generated by processes such as transcription and replication.

scholarly journals Conformational dynamics of the essential sensor histidine kinase WalK

2017 ◽  
Vol 73 (10) ◽  
pp. 793-803 ◽  
Author(s):  
Yongfei Cai ◽  
Mingyang Su ◽  
Ashfaq Ahmad ◽  
Xiaojie Hu ◽  
Jiayan Sang ◽  
...  
Keyword(s):  
Dynamic Properties ◽  
Conformational Dynamics ◽  
Bound State ◽  
Response Regulators ◽  
Histidine Kinases ◽  
Sequence Identity ◽  
Component Systems ◽  
Bacterial Signal Transduction ◽  
Two Component Systems ◽  
Intrinsic Dynamic

Two-component systems (TCSs) are key elements in bacterial signal transduction in response to environmental stresses. TCSs generally consist of sensor histidine kinases (SKs) and their cognate response regulators (RRs). Many SKs exhibit autokinase, phosphoryltransferase and phosphatase activities, which regulate RR activity through a phosphorylation and dephosphorylation cycle. However, how SKs perform different enzymatic activities is poorly understood. Here, several crystal structures of the minimal catalytic region of WalK, an essential SK fromLactobacillus plantarumthat shares 60% sequence identity with its homologue VicK fromStreptococcus mutans, are presented. WalK adopts an asymmetrical closed structure in the presence of ATP or ADP, in which one of the CA domains is positioned close to the DHp domain, thus leading both the β- and γ-phosphates of ATP/ADP to form hydrogen bonds to the ∊- but not the δ-nitrogen of the phosphorylatable histidine in the DHp domain. In addition, the DHp domain in the ATP/ADP-bound state has a 25.7° asymmetrical helical bending coordinated with the repositioning of the CA domain; these processes are mutually exclusive and alternate in response to helicity changes that are possibly regulated by upstream signals. In the absence of ATP or ADP, however, WalK adopts a completely symmetric open structure with its DHp domain centred between two outward-reaching CA domains. In summary, these structures of WalK reveal the intrinsic dynamic properties of an SK structure as a molecular basis for multifunctionality.

Multidimensional epistasis and fitness landscapes in enzyme evolution

2012 ◽  
Vol 445 (1) ◽  
pp. 39-46 ◽  
Author(s):  
Wei Zhang ◽  
Daniel F. A. R. Dourado ◽  
Pedro Alexandrino Fernandes ◽  
Maria João Ramos ◽  
Bengt Mannervik
Keyword(s):  
Glutathione Transferase ◽  
Fitness Landscape ◽  
Evolutionary Process ◽  
Salient Feature ◽  
Selective Advantage ◽  
Enzyme Evolution ◽  
Conventional Analysis ◽  
Evolutionary Response ◽  
Single Protein ◽  
Evolutionary Trajectories

The conventional analysis of enzyme evolution is to regard one single salient feature as a measure of fitness, expressed in a milieu exposing the possible selective advantage at a given time and location. Given that a single protein may serve more than one function, fitness should be assessed in several dimensions. In the present study we have explored individual mutational steps leading to a triple-point-mutated human GST (glutathione transferase) A2-2 displaying enhanced activity with azathioprine. A total of eight alternative substrates were used to monitor the diverse evolutionary trajectories. The epistatic effects of the mutations on catalytic activity were variable in sign and magnitude and depended on the substrate used, showing that epistasis is a multidimensional quality. Evidently, the multidimensional fitness landscape can lead to alternative trajectories resulting in enzymes optimized for features other than the selectable markers relevant at the origin of the evolutionary process. In this manner the evolutionary response is robust and can adapt to changing environmental conditions.

Multi-substrate–activity space and quasi-species in enzyme evolution: Ohno's dilemma, promiscuity and functional orthogonality

2009 ◽  
Vol 37 (4) ◽  
pp. 740-744 ◽  
Author(s):  
Bengt Mannervik ◽  
Arna Runarsdottir ◽  
Sanela Kurtovic
Keyword(s):  
Multivariate Analysis ◽  
Directed Evolution ◽  
Enzyme Evolution ◽  
Activity Space ◽  
Glutathione Transferases ◽  
Multidimensional Space ◽  
Alternative Substrates ◽  
Catalytic Activities ◽  
Evolutionary Trajectories

A functional enzyme displays activity with at least one substrate and can be represented by a vector in substrate–activity space. Many enzymes, including GSTs (glutathione transferases), are promiscuous in the sense that they act on alternative substrates, and the corresponding vectors operate in multidimensional space. The direction of the vector is governed by the relative activities of the diverse substrates. Stochastic mutations of already existing enzymes generate populations of variants, and clusters of functionally similar mutants can serve as parents for subsequent generations of enzymes. The proper evolving unit is a functional quasi-species, which may not be identical with the ‘best’ variant in its generation. The manifestation of the quasi-species is dependent on the substrate matrix used to explore catalytic activities. Multivariate analysis is an approach to identifying quasi-species and to investigate evolutionary trajectories in the directed evolution of enzymes for novel functions.

scholarly journals Mortality and coexistence time both cause changes in predator-prey co-evolutionary dynamics

2020 ◽  
Author(s):  
Thomas Scheuerl ◽  
Veijo Kaitala
Keyword(s):  
Evolutionary Dynamics ◽  
Evolutionary Process ◽  
Mortality Rates ◽  
Predator Prey ◽  
Ecological Changes ◽  
Evolutionary Changes ◽  
Predation Efficiency ◽  
Evolutionary Trajectories ◽  
Predator Defence ◽  
Transfer Interval

AbstractAll organisms are sensitive to the abiotic environment, and in multispecies communities a deteriorating environment increasing mortality and limiting coexistence time can cause ecological changes. When interaction within the community is changed this can impact co-evolutionary processes. Here we use a mathematical model to predict ecological and evolutionary changes in a simple predator-prey community under different mortality rates and times of coexistence, both controlled by various transfer volume and transfer interval. In the simulated bacteria-ciliate system, we find species densities to be surprisingly robust under changed mortality rates and times both species coexist, resulting in stable densities. Confirming a theoretical prediction however, the evolution of anti-predator defence in the bacteria and evolution of predation efficiency in ciliates relax under high mortalities and limited times both partners interact. In contrast, evolutionary trajectories intensify when global mortalities are low, and the predator-prey community has more time for close interaction. These results provide testable hypotheses for future studies of predator-prey systems and we hope this work will help to bridge the gap in our knowledge how ecological and evolutionary process together shape composition of microbial communities.

scholarly journals Classification of protein–protein association rates based on biophysical informatics

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Kalyani Dhusia ◽  
Yinghao Wu
Keyword(s):  
Large Scale ◽  
Cross Validation ◽  
Protein Complexes ◽  
Dynamic Properties ◽  
Conformational Dynamics ◽  
Classification Model ◽  
Coarse Grained ◽  
Modeling Framework ◽  
Validation Data ◽  
Wide Range

Abstract Background Proteins form various complexes to carry out their versatile functions in cells. The dynamic properties of protein complex formation are mainly characterized by the association rates which measures how fast these complexes can be formed. It was experimentally observed that the association rates span an extremely wide range with over ten orders of magnitudes. Identification of association rates within this spectrum for specific protein complexes is therefore essential for us to understand their functional roles. Results To tackle this problem, we integrate physics-based coarse-grained simulations into a neural-network-based classification model to estimate the range of association rates for protein complexes in a large-scale benchmark set. The cross-validation results show that, when an optimal threshold was selected, we can reach the best performance with specificity, precision, sensitivity and overall accuracy all higher than 70%. The quality of our cross-validation data has also been testified by further statistical analysis. Additionally, given an independent testing set, we can successfully predict the group of association rates for eight protein complexes out of ten. Finally, the analysis of failed cases suggests the future implementation of conformational dynamics into simulation can further improve model. Conclusions In summary, this study demonstrated that a new modeling framework that combines biophysical simulations with bioinformatics approaches is able to identify protein–protein interactions with low association rates from those with higher association rates. This method thereby can serve as a useful addition to a collection of existing experimental approaches that measure biomolecular recognition.

scholarly journals Modulation of conformational equilibrium by phosphorylation underlies the activation of deubiquitinase A

2020 ◽  
Vol 295 (12) ◽  
pp. 3945-3951 ◽  
Author(s):  
Ashish Kabra ◽  
Efsita Rumpa ◽  
Ying Li
Keyword(s):  
Conformational Equilibrium ◽  
Dynamic Properties ◽  
Conformational Dynamics ◽  
Negative Regulator ◽  
Type I ◽  
Serine Residue ◽  
Post Translational Modifications ◽  
Cellular Processes ◽  
Catalytic Rate Constant ◽  
Conformational Properties

Deubiquitinases deconjugate ubiquitin modifications from target proteins and are involved in many cellular processes in eukaryotes. The functions of deubiquitinases are regulated by post-translational modifications, mainly phosphorylation and ubiquitination. Post-translational modifications can result in subtle changes in structural and dynamic properties, which are difficult to identify but functionally important. In this work, we used NMR spectroscopy to characterize the conformational properties of the human deubiquitinase A (DUBA), a negative regulator of type I interferon. DUBA activity is regulated by phosphorylation at a single serine residue, Ser-177. We found that the catalytic rate constant of DUBA is enhanced by phosphorylation. By comparing NMR and enzyme kinetics data among different forms of DUBA with low and high activities, we concluded that a two-state equilibrium that was present only in phosphorylated DUBA is important for DUBA activity. Our results highlight the importance of defining conformational dynamics in understanding the mechanism of DUBA activation.

Dynamics of the Metal-Cutting Process

1965 ◽  
Vol 87 (4) ◽  
pp. 429-441 ◽  
Author(s):  
Paul Albrecht
Keyword(s):  
Dynamic Response ◽  
Cutting Forces ◽  
Metal Cutting ◽  
Dynamic Properties ◽  
Chip Thickness ◽  
Cutting Process ◽  
Uncut Chip Thickness ◽  
Work Surface ◽  
Experimental Approaches ◽  
Inertia Forces

An investigation into the dynamics of the metal-cutting process has been carried out using analytical and experimental approaches. An exploratory analysis into the dynamic behavior of the cutting process revealed such dynamic properties as a loop response of the cutting forces caused by the waviness of the work surface. This finding indicates the possibility of unstable behavior of the cutting process in itself. It was possible to describe analytically the phase between the force response and fluctuations of uncut chip thickness for the case of a wavy work surface. Effects of the magnitude of the shear angle as well as of its fluctuations have been studied which make it possible to correlate the instability within the cutting process to the properties of the work material. Apart from the configuration of the cutting process, its physical properties, such as inertia forces in chip formation, have been introduced into the analysis because inertia forces, negligible at steady state, may grow significant if cutting conditions are fluctuating at higher frequencies. An experimental setup has been devised and built featuring a special design of a tool dynamometer particularly suitable for the measurement of dynamic response of the cutting forces. In the setup, a cutting tool activated by a hydraulic shaker is controlled in an average position by a feedback loop mechanism. This setup makes it possible to obtain a record of the dynamic response of cutting forces caused by the fluctuation of uncut chip thickness produced by an oscillating tool in the frequency range up to about 400 cps.

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