scholarly journals A Molecular Dynamics Approach to Explore the Intramolecular Signal Transduction of PPAR-α

2019 ◽  
Vol 20 (7) ◽  
pp. 1666 ◽  
Author(s):  
Shaherin Basith ◽  
Balachandran Manavalan ◽  
Tae Shin ◽  
Gwang Lee
Keyword(s):  
Molecular Dynamics ◽  
Bound States ◽  
Structural Information ◽  
Peroxisome Proliferator ◽  
Structural Variations ◽  
Peroxisome Proliferator Activated Receptor ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Dynamics Analyses ◽  
Signal Transductions

Dynamics and functions of the peroxisome proliferator-activated receptor (PPAR)-α are modulated by the types of ligands that bind to the orthosteric sites. While several X-ray crystal structures of PPAR-α have been determined in their agonist-bound forms, detailed structural information in their apo and antagonist-bound states are still lacking. To address these limitations, we apply unbiased molecular dynamics simulations to three different PPAR-α systems to determine their modulatory mechanisms. Herein, we performed hydrogen bond and essential dynamics analyses to identify the important residues involved in polar interactions and conformational structural variations, respectively. Furthermore, betweenness centrality network analysis was carried out to identify key residues for intramolecular signaling. The differences observed in the intramolecular signal flow between apo, agonist- and antagonist-bound forms of PPAR-α will be useful for calculating maps of information flow and identifying key residues crucial for signal transductions. The predictions derived from our analysis will be of great help to medicinal chemists in the design of effective PPAR-α modulators and additionally in understanding their regulation and signal transductions.

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 Molecular dynamics simulations reveal distinct differences in conformational dynamics and thermodynamics between the unliganded and CD4-bound states of HIV-1 gp120

2020 ◽  
Vol 22 (10) ◽  
pp. 5548-5560
Author(s):  
Yi Li ◽  
Lei Deng ◽  
Jing Liang ◽  
Guang-Heng Dong ◽  
Yuan-Ling Xia ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Bound States ◽  
Conformational Dynamics ◽  
Immunological Properties ◽  
Dynamics Simulations ◽  
Hiv Gp120 ◽  
Hiv 1

Large changes in dynamics and thermodynamics of gp120 upon CD4 binding account for the functional and immunological properties of HIV/gp120.

scholarly journals In SilicoIdentification of Potent PPAR-γAgonists from Traditional Chinese Medicine: A Bioactivity Prediction, Virtual Screening, and Molecular Dynamics Study

2014 ◽  
Vol 2014 ◽  
pp. 1-19 ◽  
Author(s):  
Kuan-Chung Chen ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Molecular Dynamics ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Virtual Screening ◽  
Prediction Models ◽  
Protein Complexes ◽  
Md Simulations ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptors ◽  
Key Residues

The peroxisome proliferator-activated receptors (PPARs) related to regulation of lipid metabolism, inflammation, cell proliferation, differentiation, and glucose homeostasis by controlling the related ligand-dependent transcription of networks of genes. They are used to be served as therapeutic targets against metabolic disorder, such as obesity, dyslipidemia, and diabetes; especially, PPAR-γis the most extensively investigated isoform for the treatment of dyslipidemic type 2 diabetes. In this study, we filter compounds of traditional Chinese medicine (TCM) using bioactivities predicted by three distinct prediction models before the virtual screening. For the top candidates, the molecular dynamics (MD) simulations were also utilized to investigate the stability of interactions between ligand and PPAR-γprotein. The top two TCM candidates, 5-hydroxy-L-tryptophan and abrine, have an indole ring and carboxyl group to form the H-bonds with the key residues of PPAR-γprotein, such as residues Ser289 and Lys367. The secondary amine group of abrine also stabilized an H-bond with residue Ser289. From the figures of root mean square fluctuations (RMSFs), the key residues were stabilized in protein complexes with 5-Hydroxy-L-tryptophan and abrine as control. Hence, we propose 5-hydroxy-L-tryptophan and abrine as potential lead compounds for further study in drug development process with the PPAR-γprotein.

scholarly journals Investigations on Binding Pattern of Kinase Inhibitors with PPARγ: Molecular Docking, Molecular Dynamic Simulations, and Free Energy Calculation Studies

PPAR Research ◽  
2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Mohit Mazumder ◽  
Prija Ponnan ◽  
Umashankar Das ◽  
Samudrala Gourinath ◽  
Haseeb Ahmad Khan ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Kinase Inhibitors ◽  
Energy Calculation ◽  
Peroxisome Proliferator ◽  
Dynamic Simulations ◽  
Peroxisome Proliferator Activated Receptor ◽  
Predictive Values ◽  
Dynamics Simulations

Peroxisome proliferator-activated receptor gamma (PPARγ) is a potential target for the treatment of several disorders. In view of several FDA approved kinase inhibitors, in the current study, we have investigated the interaction of selected kinase inhibitors with PPARγusing computational modeling, docking, and molecular dynamics simulations (MDS). The docked conformations and MDS studies suggest that the selected KIs interact with PPARγin the ligand binding domain (LBD) with high positive predictive values. Hence, we have for the first time shown the plausible binding of KIs in the PPARγligand binding site. The results obtained from these in silico investigations warrant further evaluation of kinase inhibitors as PPARγligands in vitro and in vivo.

scholarly journals Cooperative Cobinding of Synthetic and Natural Ligands to the Nuclear Receptor PPARγ

2018 ◽  
Author(s):  
Jinsai Shang ◽  
Richard Brust ◽  
Sarah A. Mosure ◽  
Jared Bass ◽  
Paola Munoz-Tello ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Peroxisome Proliferator ◽  
Binding Modes ◽  
Endogenous Ligand ◽  
Peroxisome Proliferator Activated Receptor ◽  
X Ray Crystallography ◽  
Natural Ligands ◽  
Synthetic Ligand ◽  
Dynamics Simulations ◽  
And Function

Crystal structures of peroxisome proliferator-activated receptor gamma (PPARγ) have revealed overlapping binding modes for synthetic and natural/endogenous ligands, indicating competition for the orthosteric pocket. Here we show that cobinding of a synthetic ligand to the orthosteric pocket can push natural and endogenous PPARγ ligands (fatty acids) out of the orthosteric pocket towards an alternate ligand-binding site near the functionally important omega (Ω) loop. X-ray crystallography, NMR spectroscopy, all-atom molecular dynamics simulations, and mutagenesis coupled to quantitative functional assays reveal that synthetic ligand and fatty acid cobinding can form a “ligand link” to the Ω loop and synergistically affect the structure and function of PPARγ. These findings contribute to a growing body of evidence indicating ligand binding to nuclear receptors can be more complex than the classical one-for-one orthosteric exchange of a natural or endogenous ligand with a synthetic ligand.

scholarly journals The answer lies in the energy: how simple atomistic molecular dynamics simulations may hold the key to epitope prediction on the fully glycosylated SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Stefano Serapian ◽  
Filippo Marchetti ◽  
Alice Triveri ◽  
Giulia Morra ◽  
Massimiliano Meli ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulations ◽  
Structural Information ◽  
Epitope Prediction ◽  
Spike Protein ◽  
Cell Infection ◽  
Monosaccharide Residue ◽  
Decomposition Approach ◽  
S Protein ◽  
Dynamics Simulations

AbstractBetacoronavirus SARS-CoV-2 is posing a major threat to human health and its diffusion around the world is having dire socioeconomical consequences. Thanks to the scientific community’s unprecedented efforts, the atomic structure of several viral proteins has been promptly resolved. As the crucial mediator of host cell infection, the heavily glycosylated trimeric viral Spike protein (S) has been attracting the most attention and is at the center of efforts to develop antivirals, vaccines, and diagnostic solutions.Herein, we use an energy-decomposition approach to identify antigenic domains and antibody binding sites on the fully glycosylated S protein. Crucially, all that is required by our method are unbiased atomistic molecular dynamics simulations; no prior knowledge of binding properties or ad hoc combinations of parameters/measures extracted from simulations is needed. Our method simply exploits the analysis of energy interactions between all intra-protomer aminoacid and monosaccharide residue pairs, and cross-compares them with structural information (i.e., residueresidue proximity), identifying potential immunogenic regions as those groups of spatially contiguous residues with poor energetic coupling to the rest of the protein.Our results are validated by several experimentally confirmed structures of the S protein in complex with anti- or nanobodies. We identify poorly coupled sub-domains: on the one hand this indicates their role in hosting (several) epitopes, and on the other hand indicates their involvement in large functional conformational transitions. Finally, we detect two distinct behaviors of the glycan shield: glycans with stronger energetic coupling are structurally relevant and protect underlying peptidic epitopes; those with weaker coupling could themselves be poised for antibody recognition. Predicted Immunoreactive regions can be used to develop optimized antigens (recombinant subdomains, synthetic (glyco)peptidomimetics) for therapeutic applications.

scholarly journals Alpha-Carbonic Anhydrases from Hydrothermal Vent Sources as Potential Carbon Dioxide Sequestration Agents: In Silico Sequence, Structure and Dynamics Analyses

2020 ◽  
Vol 21 (21) ◽  
pp. 8066
Author(s):  
Colleen Varaidzo Manyumwa ◽  
Reza Zolfaghari Emameh ◽  
Özlem Tastan Bishop
Keyword(s):  
Structural Analysis ◽  
Protein Design ◽  
Hydrothermal Vent ◽  
Carbon Dioxide Sequestration ◽  
Carbonic Anhydrases ◽  
Hydrogen Bond Networks ◽  
Dynamics Simulations ◽  
Key Residues ◽  
Dynamics Analyses ◽  
Interface Residues

With the increase in CO2 emissions worldwide and its dire effects, there is a need to reduce CO2 concentrations in the atmosphere. Alpha-carbonic anhydrases (α-CAs) have been identified as suitable sequestration agents. This study reports the sequence and structural analysis of 15 α-CAs from bacteria, originating from hydrothermal vent systems. Structural analysis of the multimers enabled the identification of hotspot and interface residues. Molecular dynamics simulations of the homo-multimers were performed at 300 K, 363 K, 393 K and 423 K to unearth potentially thermostable α-CAs. Average betweenness centrality (BC) calculations confirmed the relevance of some hotspot and interface residues. The key residues responsible for dimer thermostability were identified by comparing fluctuating interfaces with stable ones, and were part of conserved motifs. Crucial long-lived hydrogen bond networks were observed around residues with high BC values. Dynamic cross correlation fortified the relevance of oligomerization of these proteins, thus the importance of simulating them in their multimeric forms. A consensus of the simulation analyses used in this study suggested high thermostability for the α-CA from Nitratiruptor tergarcus. Overall, our novel findings enhance the potential of biotechnology applications through the discovery of alternative thermostable CO2 sequestration agents and their potential protein design.

scholarly journals Antibodies exhibit multiple paratope states influencing VH–VL domain orientations

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Monica L. Fernández-Quintero ◽  
Nancy D. Pomarici ◽  
Barbara A. Math ◽  
Katharina B. Kroell ◽  
Franz Waibl ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Structural Information ◽  
Conformational Transitions ◽  
Antigen Binding ◽  
Antigen Binding Site ◽  
Solution Structures ◽  
Conformational Rearrangements ◽  
Complementarity Determining Regions ◽  
Dynamics Simulations

Abstract In the last decades, antibodies have emerged as one of the most important and successful classes of biopharmaceuticals. The highest variability and diversity of an antibody is concentrated on six hypervariable loops, also known as complementarity determining regions (CDRs) shaping the antigen-binding site, the paratope. Whereas it was assumed that certain sequences can only adopt a limited set of backbone conformations, in this study we present a kinetic classification of several paratope states in solution. Using molecular dynamics simulations in combination with experimental structural information we capture the involved conformational transitions between different canonical clusters and additional dominant solution structures occurring in the micro-to-millisecond timescale. Furthermore, we observe a strong correlation of CDR loop movements. Another important aspect when characterizing different paratope states is the relative VH/VL orientation and the influence of the distinct CDR loop states on the VH/VL interface. Conformational rearrangements of the CDR loops do not only have an effect on the relative VH/VL orientations, but also influence in some cases the elbow-angle dynamics and shift the respective distributions. Thus, our results show that antibodies exist as several interconverting paratope states, each contributing to the antibody’s properties.

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