scholarly journals Inactivation and reactivation of ribonuclease A studied by computer simulation

Open Biology ◽  
2012 ◽  
Vol 2 (7) ◽  
pp. 120088 ◽  
Author(s):  
Gavin M. Seddon ◽  
Robert P. Bywater
Keyword(s):  
Molecular Dynamics ◽  
Computer Simulation ◽  
In Silico ◽  
Tertiary Structure ◽  
Md Simulations ◽  
Globular Proteins ◽  
Ribonuclease A ◽  
Amino Acid Residues ◽  
Constituent Amino Acid ◽  
Single Protein

The year 2011 marked the half-centenary of the publication of what came to be known as the Anfinsen postulate, that the tertiary structure of a folded protein is prescribed fully by the sequence of its constituent amino acid residues. This postulate has become established as a credo , and, indeed, no contradictions seem to have been found to date. However, the experiments that led to this postulate were conducted on only a single protein, bovine ribonuclease A (RNAse). We conduct molecular dynamics (MD) simulations on this protein with the aim of mimicking this experiment as well as making the methodology available for use with basically any protein. There have been many attempts to model denaturation and refolding processes of globular proteins in silico using MD, but only a few examples where disulphide-bond containing proteins were studied. We took the view that if the reductive deactivation and oxidative reactivation processes of RNAse could be modelled in silico, this would provide valuable insights into the workings of the classical Anfinsen experiment.

scholarly journals Nanomaterials Interaction with Cell Membranes: Computer Simulation Studies

2020 ◽  
pp. 189-210
Author(s):  
Alexey A. Tsukanov ◽  
Olga Vasiljeva
Keyword(s):  
Molecular Dynamics ◽  
Computer Simulation ◽  
In Silico ◽  
Antimicrobial Properties ◽  
Two Dimensional ◽  
Simulation Studies ◽  
Bacterial Membranes ◽  
In Silico Studies ◽  
Dynamics Simulations ◽  
Computer Simulation Studies

AbstractThis chapter provides a brief review of computer simulation studies on the interaction of nanomaterialswith biomembranes. The interest in this area is governed by the variety of possible biomedical applications of nanoparticles and nanomaterials as well as by the importance of understanding their possible cytotoxicity. Molecular dynamics is a flexible and versatile computer simulation tool, which allows us to research the molecular level mechanisms of nanomaterials interaction with cell or bacterial membrane, predicting in silico their behavior and estimating physicochemical properties. In particular, based on the molecular dynamics simulations, a bio-action mechanism of two-dimensional aluminum hydroxide nanostructures, termed aloohene, was discovered by the research team led by Professor S. G. Psakhie, accounting for its anticancer and antimicrobial properties. Here we review three groups of nanomaterials (NMs) based on their structure: nanoparticles (globular, non-elongated), (quasi)one-dimensional NMs (nanotube, nanofiber, nanorod) and two-dimensional NMs (nanosheet, nanolayer, nanocoated substrate). Analysis of the available in silico studies, thus can enable us a better understanding of how the geometry and surface properties of NMs govern the mechanisms of their interaction with cell or bacterial membranes.

scholarly journals In Silico Exploration of Efficacious Inhibitors for SARS-CoV-2’s Papain-like Protease

2020 ◽  
Author(s):  
Tien Huynh ◽  
Wendy Cornell ◽  
Binquan Luan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanism ◽  
In Silico ◽  
Rank Order ◽  
Md Simulations ◽  
Flexible Docking ◽  
Docking Method ◽  
Approved Drugs ◽  
Fda Approved Drugs

We applied the flexible docking method to rank-order all FDA-approved drugs as inhibitors for the papain-like protease (PLpro) of SRAS-CoV-2. We also evaluated these results using molecular dynamics (MD) simulations. From MD simulations, we unveiled the molecular mechanism for a known inhibitor rac5c's binding with PLpro. <br>

scholarly journals Molecular Insights into Human Transmembrane Protease Serine-2 (TMPS2) Inhibitors against SARS-CoV2: Homology Modelling, Molecular Dynamics, and Docking Studies

Molecules ◽  
2020 ◽  
Vol 25 (21) ◽  
pp. 5007
Author(s):  
Safaa M. Kishk ◽  
Rania M. Kishk ◽  
Asmaa S. A. Yassen ◽  
Mohamed S. Nafie ◽  
Nader A. Nemr ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Serine Protease ◽  
Tertiary Structure ◽  
Virus Disease ◽  
Homology Modelling ◽  
3D Structure ◽  
Md Simulations ◽  
Homology Model ◽  
Docking Studies ◽  
In Silico Studies

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), which caused novel corona virus disease-2019 (COVID-19) pandemic, necessitated a global demand for studies related to genes and enzymes of SARS-CoV2. SARS-CoV2 infection depends on the host cell Angiotensin-Converting Enzyme-2 (ACE2) and Transmembrane Serine Protease-2 (TMPRSS2), where the virus uses ACE2 for entry and TMPRSS2 for S protein priming. The TMPRSS2 gene encodes a Transmembrane Protease Serine-2 protein (TMPS2) that belongs to the serine protease family. There is no crystal structure available for TMPS2, therefore, a homology model was required to establish a putative 3D structure for the enzyme. A homology model was constructed using SWISS-MODEL and evaluations were performed through Ramachandran plots, Verify 3D and Protein Statistical Analysis (ProSA). Molecular dynamics simulations were employed to investigate the stability of the constructed model. Docking of TMPS2 inhibitors, camostat, nafamostat, gabexate, and sivelestat, using Molecular Operating Environment (MOE) software, into the constructed model was performed and the protein-ligand complexes were subjected to MD simulations and computational binding affinity calculations. These in silico studies determined the tertiary structure of TMPS2 amino acid sequence and predicted how ligands bind to the model, which is important for drug development for the prevention and treatment of COVID-19.

scholarly journals Three-dimensional structure of Megabalanus rosa Cement Protein 20 revealed by multi-dimensional NMR and molecular dynamics simulations

2019 ◽  
Vol 374 (1784) ◽  
pp. 20190198 ◽  
Author(s):  
Harini Mohanram ◽  
Akshita Kumar ◽  
Chandra S. Verma ◽  
Konstantin Pervushin ◽  
Ali Miserez
Keyword(s):  
Molecular Dynamics ◽  
Disulfide Bonds ◽  
Molecular Mechanisms ◽  
Tertiary Structure ◽  
Three Dimensional ◽  
Md Simulations ◽  
Dimensional Structure ◽  
Nmr Studies ◽  
Dynamics Simulations ◽  
Cement Protein

Barnacles employ a protein-based cement to firmly attach to immersed substrates. The cement proteins (CPs) have previously been identified and sequenced. However, the molecular mechanisms of adhesion are not well understood, in particular, because the three-dimensional molecular structure of CPs remained unknown to date. Here, we conducted multi-dimensional nuclear magnetic resonance (NMR) studies and molecular dynamics (MD) simulations of recombinant Megabalanus rosa Cement Protein 20 ( r MrCP20). Our NMR results show that r MrCP20 contains three main folded domain regions intervened by two dynamic loops, resulting in multiple protein conformations that exist in equilibrium. We found that 12 out of 32 Cys in the sequence engage in disulfide bonds that stabilize the β -sheet domains owing to their placement at the extremities of β -strands. Another feature unveiled by NMR is the location of basic residues in turn regions that are exposed to the solvent, playing an important role for intermolecular contact with negatively charged surfaces. MD simulations highlight a highly stable and conserved β -motif ( β 7- β 8), which may function as nuclei for amyloid-like nanofibrils previously observed in the cured adhesive cement. To the best of our knowledge, this is the first report describing the tertiary structure of an extracellular biological adhesive protein at the molecular level. This article is part of the theme issue ‘Transdisciplinary approaches to the study of adhesion and adhesives in biological systems’.

Recent Advances in the In-silico Structure-based and Ligand-based Approaches for the Design and Discovery of Agonists and Antagonists of A2A Adenosine Receptor

2019 ◽  
Vol 25 (7) ◽  
pp. 774-782 ◽  
Author(s):  
Nikhil Agrawal ◽  
Balakumar Chandrasekaran ◽  
Amal Al-Aboudi
Keyword(s):  
Molecular Dynamics ◽  
Membrane Protein ◽  
In Silico ◽  
Recent Progress ◽  
Md Simulations ◽  
Pharmacophore Modeling ◽  
A2a Adenosine Receptor ◽  
A2a Receptor ◽  
In Silico Studies ◽  
The Family

A2A receptor belongs to the family of GPCRs, which are the most abundant membrane protein family. Studies in the last few decades have shown the therapeutic applications of A2A receptor in various diseases. In the present mini-review, we have discussed the recent progress in the in-silico studies of the A2A receptor. Herein, we described the different structures of A2A receptor, the discovery of new agonists and antagonists using virtualscreening/ docking, pharmacophore modeling, and QSAR based pharmacophore modeling. We have also discussed various molecular dynamics (MD) simulations studies of A2A receptor in complex with ligands.

scholarly journals Spectroscopic and In Silico Studies on the Interaction of Substituted Pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one Derivatives with c-Myc G4-DNA

2021 ◽  
Vol 22 (11) ◽  
pp. 6028
Author(s):  
Simone Mulliri ◽  
Aatto Laaksonen ◽  
Pietro Spanu ◽  
Riccardo Farris ◽  
Matteo Farci ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
In Silico ◽  
Water Solution ◽  
Md Simulations ◽  
Anticancer Activities ◽  
Myc Oncogene ◽  
G4 Dna ◽  
In Silico Studies ◽  
Wide Range ◽  
Dynamics Simulations

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2–4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (Tms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the Tms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery.

scholarly journals Experimental and Computational Evidence for Self-Assembly of Mitochondrial UCP2 in Lipid Bilayers

2018 ◽  
Author(s):  
A. Ardalan ◽  
S. O. Uwumarenogie ◽  
M. Fish ◽  
S. Sowlati-Hashjin ◽  
M. Karttunen ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Lipid Bilayers ◽  
Self Assembly ◽  
Lipid Membranes ◽  
Proton Transport ◽  
Tertiary Structure ◽  
Recombinant Expression ◽  
Atp Synthesis ◽  
Md Simulations ◽  
Uncoupling Proteins

ABSTRACTUncoupling proteins (UCPs) are members of the mitochondrial carrier family (MCF) that transport protons across the inner mitochondrial membrane, thereby uncoupling electron transport from ATP synthesis. The stoichiometry of UCPs, and the possibility of co-existence of this protein as mono-meric and associated forms in lipid membranes remain an intriguing open question. In the current study, the tertiary structure of UCP2 was analyzed both experimentally and through molecular dynamics (MD) simulations. After recombinant expression of UCP2 in the inner membrane of E. coli, the protein was directly extracted from the bacterial membranes with a non-denaturing detergent and purified both as a pure monomer and as a mixture of monomers, dimers and tetramers. Both protein preparations were re-constituted in egg yolk lipid vesicles. Gel electrophoresis, circular dichroism spectroscopy and fluorescence methods were used to characterize the structure and the proton transport function of protein. UCP2 showed unique stable tetrameric forms in lipid bilayers. MD simulations using membrane lipids and principal component analysis support the experimental results and provided new molecular insights into the nature of noncovalent interactions in oligomeric UCP2. MD simulations indicate that UCP2 tetramers are asymmetric dimers of dimers, in which the interactions between the monomers forming the dimer are stronger than the interactions between the dimers within the tetramer. It is also shown that UCP2 has a specific tendency to form functional tetramers in lipid bilayers, capable of proton transport. The asymmetric nature of the UCP2 tetramer could act as a scaffold for regulating the activity of the monomeric units through cooperative intercommunication between these subunits. Under similar experimental conditions, the structurally comparable ADP/ATP carrier protein did not form tetramers in vesicles, implying that spontaneous tetramerization cannot be generalized to all MCF members.STATEMENT OF SIGNIFICANCESelf-assembly of membrane proteins plays a significant role in their biological function. In this article, both experimental and computational evidence are provided for spontaneous tetramerization of one of the mitochondrial uncoupling proteins (UCP2) in model lipid membranes. It is also shown that the tetrameric form of UCP2 is capable of proton transport, which leads to regulation of ATP synthesis in mitochondrion. Molecular dynamics simulations confirm the presence of asymmetric UCP2 tetramers as a potential scaffold for regulating the activity of the monomeric units through mutual intercommunication. The outcome of this study provides a solid ground for potential co-existence of monomeric and multimeric functional forms of UCPs that contributes to a deeper molecular insight into their structure and function.

scholarly journals In silico Discovery of a New Potent Inhibitor for Sterol 14-alpha Demethylase as a Promising Antifungal Drug against Aspergillus fumigatus Infection

2021 ◽  
Vol 12 (5) ◽  
pp. 5785-5796
Keyword(s):  
Aspergillus Fumigatus ◽  
In Silico ◽  
Md Simulation ◽  
Potent Inhibitor ◽  
High Specificity ◽  
Md Simulations ◽  
Opportunistic Pathogen ◽  
Amino Acid Residues ◽  
Human Beings ◽  
Heme Group

Aspergillus fumigatus is a dangerous opportunistic pathogen that causes severe consequences for human beings when its conidia are inhaled. Several inhibitory drugs have recently been suggested to eradicate these fungi by inhibiting the cytochrome P450 sterol 14-alpha demethylase B (CYP51B). These drugs are designed to exhibit high specificity to the heme that is incorporated in the active site of this enzyme. Though effective binding with heme can be achieved, administration of these drugs can be accompanied by variable risks to the user’s health. Series of in silico screenings were conducted to find out more eligible drug-like compounds to inhibit CYP51B-heme with fewer side effects on patients. Using stringent ZINCPharmer restrictions, seventeen compounds were found to have efficient binding to the heme group of CYP51B. Their effectiveness against CYP51B was tested using molecular docking, drug-likeness prediction, and molecular dynamics (MD) simulation. One compound (ZINC000015774018 or molecule-8) was found to inhibit the heme group with better drug-likeness than that found in the other sixteen drug-like compounds. MD simulations showed that this ligand introduced stabilized interactions with the targeted protein upon interacting with its heme and amino acid residues. Thus it may be used as a potent antifungal inhibitor against A. fumigatus.

scholarly journals In Silico Exploration of Efficacious Inhibitors for SARS-CoV-2’s Papain-like Protease

2020 ◽  
Author(s):  
Tien Huynh ◽  
Wendy Cornell ◽  
Binquan Luan
Keyword(s):  
Molecular Dynamics ◽  
Molecular Mechanism ◽  
In Silico ◽  
Rank Order ◽  
Md Simulations ◽  
Flexible Docking ◽  
Docking Method ◽  
Approved Drugs ◽  
Fda Approved Drugs

We applied the flexible docking method to rank-order all FDA-approved drugs as inhibitors for the papain-like protease (PLpro) of SRAS-CoV-2. We also evaluated these results using molecular dynamics (MD) simulations. From MD simulations, we unveiled the molecular mechanism for a known inhibitor rac5c's binding with PLpro. <br>

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