scholarly journals Population dynamics and structural effects at short and long range support the hypothesis of the selective advantage of the G614 SARS-Cov2 spike variant

2021 ◽  
Author(s):  
Emiliano Trucchi ◽  
Paolo Gratton ◽  
Fabrizio Mafessoni ◽  
Stefano Motta ◽  
Francesco Cicconardi ◽  
...  
Keyword(s):  
Long Range ◽  
Structural Information ◽  
Selective Advantage ◽  
Clinical Samples ◽  
Range Effect ◽  
Stochastic Effects ◽  
Genomic Variants ◽  
Proteolytic Site ◽  
Conformational Plasticity ◽  
Dynamics Simulations

Abstract SARS-CoV-2 epidemics quickly propagated worldwide, sorting virus genomic variants in newly established propagules of infections. Stochasticity in transmission within and between countries or an actual selective advantage could explain the global high frequency reached by some genomic variants. Using statistical analyses, demographic reconstructions, and molecular dynamics simulations, we show that the globally invasive G614 spike variant i) underwent a significant demographic expansion in most countries not explained by stochastic effects nor by overrepresentation in clinical samples; ii) increases the spike S1/S2 furin-like site conformational plasticity (short-range effect), and iii) modifies the internal motion of the receptor-binding domain affecting its cross-connection with other functional domains (long-range effect). Our results support the hypothesis of a selective advantage at the basis of the spread of the G614 variant, which we suggest may be due to structural modification of the spike protein at the S1/S2 proteolytic site, and provides structural information to guide the design of variant-specific drugs.

scholarly journals Unveiling diffusion pattern and structural impact of the most invasive SARS-CoV-2 spike mutation

2020 ◽  
Author(s):  
Emiliano Trucchi ◽  
Paolo Gratton ◽  
Fabrizio Mafessoni ◽  
Stefano Motta ◽  
Francesco Cicconardi ◽  
...  
Keyword(s):  
Structural Information ◽  
Transmission Rate ◽  
Selective Advantage ◽  
Spike Protein ◽  
Range Effect ◽  
Protein Variant ◽  
Statistical Population ◽  
Genomic Variants ◽  
Theoretical Approaches ◽  
Diffusion Pattern

ABSTRACTStarting in Wuhan, China, SARS-CoV-2 epidemics quickly propagated worldwide in less than three months, geographically sorting genomic variants in newly established propagules of infections. Stochasticity in transmission within and between countries and/or actual advantage in virus transmissibility could explain the high frequency reached by some genomic variants during the course of the outbreak.Using a suite of statistical, population genetics, and theoretical approaches, we show that the globally most represented spike protein variant (i.e., the G clade, A → G nucleotide change at genomic position 23,403; D → G amino acid change at spike protein position 614) i) underwent a significant demographic expansion in most countries not explained by stochastic effects or enhanced pathogenicity; ii) affects the spike S1/S2 furin-like site increasing its conformational plasticity (short range effect), and iii) modifies the internal motion of the receptor-binding domain affecting its cross-connection with other functional domains (long-range effect).Our study unambiguously links the spread of the G614 with a non-random process, and we hypothesize that this process is related to the selective advantage produced by a specific structural modification of the spike protein. We conclude that the different conformation of the S1/S2 proteolytic site is at the basis of the higher transmission rate of this invasive SARS-CoV-2 variant, and provide structural information to guide the design of selective and efficient drugs.

Use of Molecular Dynamics Simulations in Structure-Based Drug Discovery

2019 ◽  
Vol 25 (31) ◽  
pp. 3339-3349 ◽  
Author(s):  
Indrani Bera ◽  
Pavan V. Payghan
Keyword(s):  
Molecular Dynamics ◽  
Drug Discovery ◽  
Molecular Dynamics Simulations ◽  
Drug Target ◽  
Structural Information ◽  
Drug Binding ◽  
Structure Based Drug Design ◽  
Drug Designing ◽  
Target Binding ◽  
Dynamics Simulations

Background: Traditional drug discovery is a lengthy process which involves a huge amount of resources. Modern-day drug discovers various multidisciplinary approaches amongst which, computational ligand and structure-based drug designing methods contribute significantly. Structure-based drug designing techniques require the knowledge of structural information of drug target and drug-target complexes. Proper understanding of drug-target binding requires the flexibility of both ligand and receptor to be incorporated. Molecular docking refers to the static picture of the drug-target complex(es). Molecular dynamics, on the other hand, introduces flexibility to understand the drug binding process. Objective: The aim of the present study is to provide a systematic review on the usage of molecular dynamics simulations to aid the process of structure-based drug design. Method: This review discussed findings from various research articles and review papers on the use of molecular dynamics in drug discovery. All efforts highlight the practical grounds for which molecular dynamics simulations are used in drug designing program. In summary, various aspects of the use of molecular dynamics simulations that underline the basis of studying drug-target complexes were thoroughly explained. Results: This review is the result of reviewing more than a hundred papers. It summarizes various problems that use molecular dynamics simulations. Conclusion: The findings of this review highlight how molecular dynamics simulations have been successfully implemented to study the structure-function details of specific drug-target complexes. It also identifies the key areas such as stability of drug-target complexes, ligand binding kinetics and identification of allosteric sites which have been elucidated using molecular dynamics simulations.

scholarly journals Pervasive cooperative mutational effects on multiple catalytic enzyme traits emerge via long-range conformational dynamics

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Carlos G. Acevedo-Rocha ◽  
Aitao Li ◽  
Lorenzo D’Amore ◽  
Sabrina Hoebenreich ◽  
Joaquin Sanchis ◽  
...  
Keyword(s):  
Long Range ◽  
Fitness Landscape ◽  
Conformational Dynamics ◽  
P450 Monooxygenase ◽  
Access Channel ◽  
Long Range Interactions ◽  
Limited Protein ◽  
Dynamics Simulations ◽  
The Relationship ◽  
Single Enzyme

AbstractMultidimensional fitness landscapes provide insights into the molecular basis of laboratory and natural evolution. To date, such efforts usually focus on limited protein families and a single enzyme trait, with little concern about the relationship between protein epistasis and conformational dynamics. Here, we report a multiparametric fitness landscape for a cytochrome P450 monooxygenase that was engineered for the regio- and stereoselective hydroxylation of a steroid. We develop a computational program to automatically quantify non-additive effects among all possible mutational pathways, finding pervasive cooperative signs and magnitude epistasis on multiple catalytic traits. By using quantum mechanics and molecular dynamics simulations, we show that these effects are modulated by long-range interactions in loops, helices and β-strands that gate the substrate access channel allowing for optimal catalysis. Our work highlights the importance of conformational dynamics on epistasis in an enzyme involved in secondary metabolism and offers insights for engineering P450s.

scholarly journals Long-range effect of cyanide on mercury methylation in a gold mining area in southern Ecuador

2011 ◽  
Vol 409 (23) ◽  
pp. 5026-5033 ◽  
Author(s):  
Jean Remy Davée Guimaraes ◽  
Oscar Betancourt ◽  
Marcio Rodrigues Miranda ◽  
Ramiro Barriga ◽  
Edwin Cueva ◽  
...  
Keyword(s):  
Long Range ◽  
Gold Mining ◽  
Mining Area ◽  
Mercury Methylation ◽  
Range Effect ◽  
Southern Ecuador

SERS ? A long-range effect?

1989 ◽  
Vol 49 (4) ◽  
pp. 389-391 ◽  
Author(s):  
I. Mrozek ◽  
A. Otto
Keyword(s):  
Long Range ◽  
Range Effect

scholarly journals Automated and optimally FRET-assisted structural modeling

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Mykola Dimura ◽  
Thomas-Otavio Peulen ◽  
Hugo Sanabria ◽  
Dmitro Rodnin ◽  
Katherina Hemmen ◽  
...  
Keyword(s):  
Open Source Software ◽  
Structural Information ◽  
Structural Modeling ◽  
Automated Design ◽  
Design Tool ◽  
Coarse Grained ◽  
Complex Dynamic ◽  
X Ray ◽  
Link Type ◽  
Dynamics Simulations

Abstract FRET experiments can provide state-specific structural information of complex dynamic biomolecular assemblies. However, to overcome the sparsity of FRET experiments, they need to be combined with computer simulations. We introduce a program suite with (i) an automated design tool for FRET experiments, which determines how many and which FRET pairs should be used to minimize the uncertainty and maximize the accuracy of an integrative structure, (ii) an efficient approach for FRET-assisted coarse-grained structural modeling, and all-atom molecular dynamics simulations-based refinement, and (iii) a quantitative quality estimate for judging the accuracy of FRET-derived structures as opposed to precision. We benchmark our tools against simulated and experimental data of proteins with multiple conformational states and demonstrate an accuracy of ~3 Å RMSDCα against X-ray structures for sets of 15 to 23 FRET pairs. Free and open-source software for the introduced workflow is available at https://github.com/Fluorescence-Tools. A web server for FRET-assisted structural modeling of proteins is available at http://nmsim.de.

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