ConSurf‐DB: An accessible repository for the evolutionary conservation patterns of the majority of PDB proteins

Chorin, Adi Ben; Masrati, Gal; Kessel, Amit; Narunsky, Aya; Sprinzak, Josef; Lahav, Shlomtzion; Ashkenazy, Haim; Ben‐Tal, Nir

doi:10.1002/pro.3779

Cited by 129 publications

(138 citation statements)

References 45 publications

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“…To understand the interplay between evolutionary, topological, and dynamic signatures of the SARS-CoV-2 spike glycoprotein trimer, the sequence conservation profiles are computed to identify regions of high conservation and variability ( Figure 3 ). The sequence conservation ConSurf approach 52 − 56 was used to determine the residue-based conservation score profiles in which the low score is associated with the most conserved position in the protein. Consistent with previous studies, 108 − 110 this analysis showed that residues in the S1 domain are considerably less conserved than the S2 fusion domain.…”

Section: Resultsmentioning

confidence: 99%

Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins

Verkhivker

2020

J. Proteome Res.

114

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The development of computational strategies for the quantitative characterization of the functional mechanisms of SARS-CoV-2 spike proteins is of paramount importance in efforts to accelerate the discovery of novel therapeutic agents and vaccines combating the COVID-19 pandemic. Structural and biophysical studies have recently characterized the conformational landscapes of the SARS-CoV-2 spike glycoproteins in the prefusion form, revealing a spectrum of stable and more dynamic states. By employing molecular simulations and network modeling approaches, this study systematically examined functional dynamics and identified the regulatory centers of allosteric interactions for distinct functional states of the wild-type and mutant variants of the SARS-CoV-2 prefusion spike trimer. This study presents evidence that the SARS-CoV-2 spike protein can function as an allosteric regulatory engine that fluctuates between dynamically distinct functional states. Perturbation-based modeling of the interaction networks revealed a key role of the cross-talk between the effector hotspots in the receptor binding domain and the fusion peptide proximal region of the SARS-CoV-2 spike protein. The results have shown that the allosteric hotspots of the interaction networks in the SARS-CoV-2 spike protein can control the dynamic switching between functional conformational states that are associated with virus entry to the host receptor. This study offers a useful and novel perspective on the underlying mechanisms of the SARS-CoV-2 spike protein through the lens of allosteric signaling as a regulatory apparatus of virus transmission that could open up opportunities for targeted allosteric drug discovery against SARS-CoV-2 proteins and contribute to the rapid response to the current and potential future pandemic scenarios.

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Section: Resultsmentioning

confidence: 99%

Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins

Verkhivker

2020

J. Proteome Res.

114

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“…To quantify these observations, we performed sequence alignment analysis and highlighted differences between SARS-CoV and SARS-CoV-2 sequences ( Figure 2 ). ConSurf approach has shown a robust performance in evolutionary analysis of proteins and the latest version of this method [ 38 , 39 ] was used in our study. The evolutionary analysis yielded an overall sequence identity of 78%.…”

Section: Resultsmentioning

confidence: 99%

“…Structural studies confirmed these assertions revealing small but important changes in the RBM residues of SARS-CoV-RBD and SARS-CoV-2-RBD proteins [ 21 , 22 , 23 , 24 , 25 , 26 ]. We utilized two different sequence conservation measures Consurf score [ 38 , 39 ] and KL sequence conservation score [ 43 , 44 , 45 , 46 , 47 ] to identify regions of high conservation and characterize in some details the extent of conservation and variability of the binding interface residues ( Figure 4 ). We analyzed the results of sequence analysis in the context of structural and functional information, particularly to quantify the conservation patterns of the hotspot residues and uncover evolutionary origins of SARS-CoV-2 binding selectivity with ACE2.…”

Section: Resultsmentioning

confidence: 99%

Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2

Verkhivker

2020

IJMS

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Binding to the host receptor is a critical initial step for the coronavirus SARS-CoV-2 spike protein to enter into target cells and trigger virus transmission. A detailed dynamic and energetic view of the binding mechanisms underlying virus entry is not fully understood and the consensus around the molecular origins behind binding preferences of SARS-CoV-2 for binding with the angiotensin-converting enzyme 2 (ACE2) host receptor is yet to be established. In this work, we performed a comprehensive computational investigation in which sequence analysis and modeling of coevolutionary networks are combined with atomistic molecular simulations and comparative binding free energy analysis of the SARS-CoV and SARS-CoV-2 spike protein receptor binding domains with the ACE2 host receptor. Different from other computational studies, we systematically examine the molecular and energetic determinants of the binding mechanisms between SARS-CoV-2 and ACE2 proteins through the lens of coevolution, conformational dynamics, and allosteric interactions that conspire to drive binding interactions and signal transmission. Conformational dynamics analysis revealed the important differences in mobility of the binding interfaces for the SARS-CoV-2 spike protein that are not confined to several binding hotspots, but instead are broadly distributed across many interface residues. Through coevolutionary network analysis and dynamics-based alanine scanning, we established linkages between the binding energy hotspots and potential regulators and carriers of signal communication in the virus–host receptor complexes. The results of this study detailed a binding mechanism in which the energetics of the SARS-CoV-2 association with ACE2 may be determined by cumulative changes of a number of residues distributed across the entire binding interface. The central findings of this study are consistent with structural and biochemical data and highlight drug discovery challenges of inhibiting large and adaptive protein–protein interfaces responsible for virus entry and infection transmission.

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“…For both the TRI5 p and TRI8 p structures, ConSurf-DB (ConSurf Data Base [ 88 , 89 ]; ) enabled structure modelling based on conserved sites unlike PDB structure models. Regions of high to low conservation were mapped onto the structures and a 3D rendering was generated for chain A and B depending on the enzyme.…”

Section: Methodsmentioning

confidence: 99%

Signatures of TRI5, TRI8 and TRI11 Protein Sequences of Fusarium incarnatum-equiseti Species Complex (FIESC) Indicate Differential Trichothecene Analogue Production

Villafana

Rampersad

2020

Toxins

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The variability and phylogeny among TRI5, TRI8 and TRI11 nucleotide and translated protein sequences of isolates from Trinidad belonging to Fusarium incarnatum-equiseti species complex (FIESC) were compared with FIESC reference sequences. Taxa appeared to be more divergent when DNA sequences were analyzed compared to protein sequences. Neutral and non-neutral mutations in TRI protein sequences that may correspond to variability in the function and structure of the selected TRI proteins were identified. TRI5p had the lowest amino acid diversity with zero predicted non-neutral mutations. TRI5p had potentially three protein disorder regions compared to TRI8p with five protein disorder regions. The deduced TRI11p was more conserved than TRI8p of the same strains. Amino acid substitutions that may be non-neutral to protein function were only detected in diacetoxyscirpenol (DAS) and fusarenon-X (FUS-X) producers of the reference sequence subset for TRI8p and TRI11p. The deduced TRI5 and TRI8 amino acid sequences were mapped to known 3D-structure models and indicated that variations in specific protein order/disorder regions exist in these sequences which affect the overall structural conservation of TRI proteins. Assigning single or combination non-neutral mutations to a particular toxicogenic phenotype may be more representative of potential compared to using genotypic data alone, especially in the absence of wet-lab, experimental validation.

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ConSurf‐DB: An accessible repository for the evolutionary conservation patterns of the majority of PDB proteins

Cited by 129 publications

References 45 publications

Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins

Molecular Simulations and Network Modeling Reveal an Allosteric Signaling in the SARS-CoV-2 Spike Proteins

Coevolution, Dynamics and Allostery Conspire in Shaping Cooperative Binding and Signal Transmission of the SARS-CoV-2 Spike Protein with Human Angiotensin-Converting Enzyme 2

Signatures of TRI5, TRI8 and TRI11 Protein Sequences of Fusarium incarnatum-equiseti Species Complex (FIESC) Indicate Differential Trichothecene Analogue Production

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