scholarly journals Unveiling Mutation Effects on the Structural Dynamics of the Main Protease from SARS-CoV-2 with Hybrid Simulation Methods

2021 ◽  
Author(s):  
Eric Allison Philot ◽  
Patricia Gasparini ◽  
Jean Carlos de Mattos ◽  
Angelo Magro ◽  
Enndrew Torres-Bonfim ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Hybrid Methods ◽  
Hybrid Approach ◽  
Hybrid Simulation ◽  
Simulation Method ◽  
Accessible Surface Area ◽  
Conformational Space ◽  
Solvent Accessible Surface Area ◽  
Complex Structural ◽  
Global Movements

In this article, we used a hybrid simulation method to sample the conformational space to characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutants, including several mutations that appear in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. Integrated Hybrid methods combining NMA and MD have been useful to study the correlation between the complex structural dynamics of macromolecules and their functioning mechanisms. Here, we applied this hybrid approach to elucidate the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro, considering their flexibility, solvent accessible surface area analyses, global movements, and catalytic dyad distance. Furthermore, some mutants showed significant changes in their structural dynamics and conformation, which could lead to distinct functional properties.

scholarly journals Unveiling Mutation Effects on the Structural Dynamics of the Main Protease from SARS-CoV-2 with Hybrid Simulation Methods

2021 ◽  
Author(s):  
Eric Philot ◽  
Angelo Magro ◽  
Patrícia Ggasparini ◽  
Jean Carlos de Mattos ◽  
Natanael Endrew Torres-Bonfim ◽  
...  
Keyword(s):  
Structural Dynamics ◽  
Hybrid Methods ◽  
Normal Mode Analysis ◽  
Hybrid Approach ◽  
Hybrid Simulation ◽  
Conformational Space ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Main Protease ◽  
Complex Structural

The main protease of SARS-CoV-2 (called Mpro or 3CLpro) is essential for processing polyproteins encoded by viral RNA. Macromolecules adopt several favored conformations in solution depending on their structure and shape, determining their dynamics and function. Integrated methods combining the lowest-frequency movements obtained by Normal Mode Analysis (NMA), and the faster movements from Molecular Dynamics (MD), and data from biophysical techniques, are necessary to establish the correlation between complex structural dynamics of macromolecules and their function. In this article, we used a hybrid simulation method to sample the conformational space to characterize the structural dynamics and global motions of WT SARS-CoV-2 Mpro and 48 mutants, including several mutations that appear in P.1, B.1.1.7, B.1.351, B.1.525 and B.1.429+B.1.427 variants. Integrated Hybrid methods combining NMA and MD have been useful to study the correlation between the complex structural dynamics of macromolecules and their functioning mechanisms. Here, we applied this hybrid approach to elucidate the effects of mutation in the structural dynamics of SARS-CoV-2 Mpro, considering their flexibility, solvent accessible surface area analyses, global movements, and catalytic dyad distance. Furthermore, some mutants showed significant changes in their structural dynamics and conformation, which could lead to distinct functional properties.

Application of the ESMACS Binding Free Energy Protocol to a Highly Varied Ligand Dataset: Lactate Dehydogenase A

2019 ◽  
Author(s):  
David Wright ◽  
Fouad Husseini ◽  
Shunzhou Wan ◽  
Christophe Meyer ◽  
Herman Van Vlijmen ◽  
...  
Keyword(s):  
Free Energy ◽  
Surface Area ◽  
Binding Free Energy ◽  
Normal Mode Analysis ◽  
Binding Mode ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Mode Analysis ◽  
Energy Calculation ◽  
Accessible Surface

<div>Here, we evaluate the performance of our range of ensemble simulation based binding free energy calculation protocols, called ESMACS (enhanced sampling of molecular dynamics with approximation of continuum solvent) for use in fragment based drug design scenarios. ESMACS is designed to generate reproducible binding affinity predictions from the widely used molecular mechanics Poisson-Boltzmann surface area (MMPBSA) approach. We study ligands designed to target two binding pockets in the lactate dehydogenase A target protein, which vary in size, charge and binding mode. When comparing to experimental results, we obtain excellent statistical rankings across this highly diverse set of ligands. In addition, we investigate three approaches to account for entropic contributions not captured by standard MMPBSA calculations: (1) normal mode analysis, (2) weighted solvent accessible surface area (WSAS) and (3) variational entropy. </div>

The Molecular and Enzyme Kinetic Basis for Altered Activity of Three Cytochrome P450 2C19 Variants Found in the Chinese Population

2020 ◽  
Vol 13 (3) ◽  
pp. 233-244
Author(s):  
Amelia Nathania Dong ◽  
Nafees Ahemad ◽  
Yan Pan ◽  
Uma Devi Palanisamy ◽  
Beow Chin Yiap ◽  
...  
Keyword(s):  
Cytochrome P450 ◽  
Molecular Docking ◽  
Active Site ◽  
Chinese Population ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
In Vitro Assays ◽  
Access Channel ◽  
Cytochrome P450 2C19

Background: There is a large inter-individual variation in cytochrome P450 2C19 (CYP2C19) activity. The variability can be caused by the genetic polymorphism of CYP2C19 gene. This study aimed to investigate the molecular and kinetics basis for activity changes in three alleles including CYP2C19*23, CYP2C19*24 and CYP2C19*25found in the Chinese population. Methods: The three variants expressed by bacteria were investigated using substrate (omeprazole and 3- cyano-7-ethoxycoumarin[CEC]) and inhibitor (ketoconazole, fluoxetine, sertraline and loratadine) probes in enzyme assays along with molecular docking. Results: All alleles exhibited very low enzyme activity and affinity towards omeprazole and CEC (6.1% or less in intrinsic clearance). The inhibition studies with the four inhibitors, however, suggested that mutations in different variants have a tendency to cause enhanced binding (reduced IC50 values). The enhanced binding could partially be explained by the lower polar solvent accessible surface area of the inhibitors relative to the substrates. Molecular docking indicated that G91R, R335Q and F448L, the unique mutations in the alleles, have caused slight alteration in the substrate access channel morphology and a more compact active site cavity hence affecting ligand access and binding. It is likely that these structural alterations in CYP2C19 proteins have caused ligand-specific alteration in catalytic and inhibitory specificities as observed in the in vitro assays. Conclusion: This study indicates that CYP2C19 variant selectivity for ligands was not solely governed by mutation-induced modifications in the active site architecture, but the intrinsic properties of the probe compounds also played a vital role.

scholarly journals Folding and Intrinsic Disorder of the Receptor Tyrosine Kinase KIT Insert Domain Seen by Conventional Molecular Dynamics Simulations

2021 ◽  
Vol 22 (14) ◽  
pp. 7375
Author(s):  
Julie Ledoux ◽  
Alain Trouvé ◽  
Luba Tchertanov
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Tertiary Structure ◽  
Average Distance ◽  
Intrinsic Disorder ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
Hydrophobic Core ◽  
Direct Evaluation ◽  
Dynamics Simulations

The kinase insert domain (KID) of RTK KIT is the key recruitment region for downstream signalling proteins. KID, studied by molecular dynamics simulations as a cleaved polypeptide and as a native domain fused to KIT, showed intrinsic disorder represented by a set of heterogeneous conformations. The accurate atomistic models showed that the helical fold of KID is mainly sequence dependent. However, the reduced fold of the native KID suggests that its folding is allosterically controlled by the kinase domain. The tertiary structure of KID represents a compact array of highly variable α- and 310-helices linked by flexible loops playing a principal role in the conformational diversity. The helically folded KID retains a collapsed globule-like shape due to non-covalent interactions associated in a ternary hydrophobic core. The free energy landscapes constructed from first principles—the size, the measure of the average distance between the conformations, the amount of helices and the solvent-accessible surface area—describe the KID disorder through a collection of minima (wells), providing a direct evaluation of conformational ensembles. We found that the cleaved KID simulated with restricted N- and C-ends better reproduces the native KID than the isolated polypeptide. We suggest that a cyclic, generic KID would be best suited for future studies of KID f post-transduction effects.

scholarly journals PAMAM dendrimer: a pH-controlled nanosponge

2017 ◽  
Vol 95 (9) ◽  
pp. 991-998 ◽  
Author(s):  
Prabal K. Maiti
Keyword(s):  
Accessible Surface Area ◽  
Pamam Dendrimer ◽  
Low Ph ◽  
Dynamics Simulation ◽  
Solvent Accessible Surface Area ◽  
Water Molecules ◽  
Accessible Volume ◽  
Accessible Surface ◽  
Solvent Accessible Surface ◽  
Ph Controlled

Using fully atomistic molecular dynamics simulation that are several hundred nanoseconds long, we demonstrate the pH-controlled sponge action of PAMAM dendrimer. We show how at varying pH levels, the PAMAM dendrimer acts as a wet sponge; at neutral or low pH levels, the dendrimer expands noticeably and the interior of the dendrimer opens up to host several hundreds to thousands of water molecules depending on the generation number. Increasing the pH (i.e., going from low pH to high pH) leads to the collapse of the dendrimer size, thereby expelling the inner water, which mimics the ‘sponge’ action. As the dendrimer size swells up at a neutral pH or low pH due to the electrostatic repulsion between the primary and tertiary amines that are protonated at this pH, there is dramatic increase in the available solvent accessible surface area (SASA), as well as solvent accessible volume (SAV).

scholarly journals Development of a hybrid simulation method for current collection systems, using a real-time multi degree-of-freedom catenary model

2018 ◽  
Vol 84 (867) ◽  
pp. 18-00229-18-00229
Author(s):  
Shigeyuki KOBAYASHI ◽  
Yoshitaka YAMASHITA ◽  
Takayuki USUDA ◽  
David P. STOTEN
Keyword(s):  
Real Time ◽  
Hybrid Simulation ◽  
Simulation Method ◽  
Degree Of Freedom ◽  
Current Collection

scholarly journals B-Cell Epitope Discovery: The First Protein Flexibility-Based Algorithm – Zika Virus Conserved Epitope Demonstration

2020 ◽  
Author(s):  
Daniel W. Biner ◽  
Jason S. Grosch ◽  
Peter J. Ortoleva
Keyword(s):  
B Cell ◽  
Zika Virus ◽  
Clustering Algorithm ◽  
Cell Epitope ◽  
Protein Flexibility ◽  
Accessible Surface Area ◽  
Solvent Accessible Surface Area ◽  
B Cell Epitopes ◽  
Enveloped Virus ◽  
Epitope Discovery

<p></p><p>Antibody-antigen interaction – at antigenic local environments called B-cell epitopes – is a prominent mechanism for neutralization of infection. Effective mimicry, and display, of B-cell epitopes is key to vaccine design. Here, a physical approach is evaluated for the discovery of epitopes which evolve slowly over closely related pathogens (conserved epitopes). The approach is 1) protein flexibility-based and 2) demonstrated with clinically relevant enveloped viruses, simulated via molecular dynamics. The approach is validated against 1) seven structurally characterized enveloped virus epitopes which evolved the least (out of thirty-eight enveloped virus-antibody structures) and 2) eight preexisting epitope and peptide discovery algorithms. Rationale for a new benchmarking scheme is presented. A data-driven epitope clustering algorithm is introduced. The prediction of eleven Zika virus epitopes (for future exploration on recombinant vaccine technologies) is demonstrated. For the first time, protein flexibility is shown to outperform solvent accessible surface area as an epitope discovery metric.</p><p></p>

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