scholarly journals Site‒specific IR spectroscopy and molecular modelling combined towards solving transmembrane protein structure

2005 ◽  
Vol 19 (1) ◽  
pp. 1-16 ◽  
Author(s):  
Andreas Kukol
Keyword(s):  
Molecular Dynamics ◽  
Mhc Class Ii ◽  
Transmembrane Protein ◽  
Protein Structures ◽  
Critical Evaluation ◽  
Dynamics Simulation ◽  
Proton Channel ◽  
Conformational Search ◽  
Widespread Application ◽  
Site Specific

Membrane protein structures are underrepresented in structural databases despite their abundance and biomedical importance. This review focuses on the novel method of site-specific infrared dichroism (SSID) combined with constraint molecular dynamics simulation, which has recently emerged as a powerful method to obtain structures of transmembrane α-helical bundles. The theory of SSID including its latest developments is reviewed with the aim to encourage widespread application of this method. This is followed by an outline of the conformational search using experimentally constraint molecular dynamics simulations. Finally a critical evaluation of recent applications, namely the Influenza M2 proton channel, the vpu ion channel of HIV-1 and the MHC-class II associated invariant chain, is conducted.

Improved Sampling Strategies for Protein Model Refinement based on Molecular Dynamics Simulation

2020 ◽  
Author(s):  
Lim Heo ◽  
Collin Arbour ◽  
Michael Feig
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Structure Prediction ◽  
Protein Structures ◽  
Conformational Space ◽  
Dynamics Simulation ◽  
Model Refinement ◽  
Protein Model ◽  
Lower Accuracy ◽  
Simulation Based

Protein structures provide valuable information for understanding biological processes. Protein structures can be determined by experimental methods such as X-ray crystallography, nuclear magnetic resonance (NMR) spectroscopy, or cryogenic electron microscopy. As an alternative, in silico methods can be used to predict protein structures. Those methods utilize protein structure databases for structure prediction via template-based modeling or for training machine-learning models to generate predictions. Structure prediction for proteins distant from proteins with known structures often results in lower accuracy with respect to the true physiological structures. Physics-based protein model refinement methods can be applied to improve model accuracy in the predicted models. Refinement methods rely on conformational sampling around the predicted structures, and if structures closer to the native states are sampled, improvements in the model quality become possible. Molecular dynamics simulations have been especially successful for improving model qualities but although consistent refinement can be achieved, the improvements in model qualities are still moderate. To extend the refinement performance of a simulation-based protocol, we explored new schemes that focus on an optimized use of biasing functions and the application of increased simulation temperatures. In addition, we tested the use of alternative initial models so that the simulations can explore conformational space more broadly. Based on the insight of this analysis we are proposing a new refinement protocol that significantly outperformed previous state-of-the-art molecular dynamics simulation-based protocols in the benchmark tests described here. <br>

scholarly journals Molecular Dynamics Simulation Studies of Ion Permeation Pathways and Energetics in the Hv1 Proton Channel

2013 ◽  
Vol 104 (2) ◽  
pp. 276a
Author(s):  
Mona L. Wood ◽  
Greg Starek ◽  
J. Alfredo Freites ◽  
Stephen H. White ◽  
I-Feng William Kuo ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Dynamics Simulation ◽  
Proton Channel ◽  
Ion Permeation ◽  
Simulation Studies

scholarly journals Blind protein structure prediction using accelerated free-energy simulations

2016 ◽  
Vol 2 (11) ◽  
pp. e1601274 ◽  
Author(s):  
Alberto Perez ◽  
Joseph A. Morrone ◽  
Emiliano Brini ◽  
Justin L. MacCallum ◽  
Ken A. Dill
Keyword(s):  
Molecular Dynamics ◽  
Structure Prediction ◽  
Protein Structures ◽  
Critical Assessment ◽  
Dynamics Simulation ◽  
Limited Data ◽  
Native Protein ◽  
Acceleration Method ◽  
Energy Simulations ◽  
Proof Of Principle

We report a key proof of principle of a new acceleration method [Modeling Employing Limited Data (MELD)] for predicting protein structures by molecular dynamics simulation. It shows that such Boltzmann-satisfying techniques are now sufficiently fast and accurate to predict native protein structures in a limited test within the Critical Assessment of Structure Prediction (CASP) community-wide blind competition.

scholarly journals Molecular dynamics simulation and docking studies reveal NF-κB as a promising therapeutic drug target for COVID-19

2021 ◽  
Author(s):  
Shaban Ahmad ◽  
Piyush Bhanu ◽  
Jitendra Kumar ◽  
Ravi Kant Pathak ◽  
Dharmendra Mallick ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Protein Structures ◽  
Drug Repurposing ◽  
Docking Studies ◽  
Dynamics Simulation ◽  
Spike Protein ◽  
Drug Candidate ◽  
Therapeutic Drug ◽  
Ligand Complex

Abstract Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is rampant worldwide and is a deadly disease for humans. Our current work emphasizes on molecular dynamics simulation (MDS) targeting nuclear factor-kappa B (NF-κB), the well-known human transcription factor controlling innate and adaptive immunity, to understand its mechanism of action during COVID-19 in humans. NF-κB was interacted with the SARS-CoV-2 spike protein in an in silico MDS experiment, revealing the NF-κB site at which the SARS-CoV-2 spike protein interacts. We screened some known drugs via docking studies on NF-κB used as a receptor. The MDS software Schrodinger generated more than 2000 complexes from these compounds and using the SMILES format of these complexes, 243 structures were extracted and 411 conformers were generated. The drug used as a ligand that docked with NF-κB with the best docking score and binding affinity was Sulindac sodium as its trade name. Furthermore, RMSF data of sulindac sodium and NF-κB displayed minimal fluctuations in the protein structures, and the protein-ligand complex had reduced flexibility. Sulindac sodium is hence suggested as a suitable drug candidate for repurposing in clinical trials for SARS-CoV-2 infections. This drug potently blocked the spike protein’s interaction with NF-κB by inducing a conformational change in the latter. Arguably, NF-κB inaction is desired to have normal immunity and can possibly be retained using proposed drug. This work provides a significant lead for drug repurposing to combat SARS-CoV-2 and its various mutant forms and reveals new approach for controlling SARS-CoV-2-induced disease.

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