scholarly journals Using Protein Homology Models for Structure-Based Studies: Approaches to Model Refinement

2006 ◽  
Vol 6 ◽  
pp. 1542-1554 ◽  
Author(s):  
V. Kairys ◽  
M.K. Gilson ◽  
Miguel Xavier Fernandes
Keyword(s):  
Experimental Data ◽  
Homology Model ◽  
Target Protein ◽  
Protein Homology ◽  
Model Refinement ◽  
Sequence Identity ◽  
Computational Methodology ◽  
Backbone Atoms ◽  
Homology Models ◽  
Template Protein

Homology modeling is a computational methodology to assign a 3-D structure to a target protein when experimental data are not available. The methodology uses another protein with a known structure that shares some sequence identity with the target as a template. The crudest approach is to thread the target protein backbone atoms over the backbone atoms of the template protein, but necessary refinement methods are needed to produce realistic models. In this mini-review anchored within the scope of drug design, we show the validity of using homology models of proteins in the discovery of binders for potential therapeutic targets. We also report several different approaches to homology model refinement, going from very simple to the most elaborate. Results show that refinement approaches are system dependent and that more elaborate methodologies do not always correlate with better performances from built homology models.

scholarly journals Illustrating and homology modeling the proteins of the Zika virus

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 275 ◽  
Author(s):  
Sean Ekins ◽  
John Liebler ◽  
Bruno J. Neves ◽  
Warren G. Lewis ◽  
Megan Coffee ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Crystal Structures ◽  
Zika Virus ◽  
Antiviral Drug ◽  
Homology Model ◽  
Model Quality ◽  
Glycoprotein E ◽  
Starting Point ◽  
Homology Models

The Zika virus (ZIKV) is a flavivirus of the familyFlaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it eitherin vitroorin vivo. ZIKV therefore epitomizes a neglected disease. Several suggested steps have been proposed which could be taken to initiate ZIKV antiviral drug discovery using both high throughput screens as well as structure-based design based on homology models for the key proteins. We now describe preliminary homology models created for NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E using SWISS-MODEL. Eleven out of 15 models pass our model quality criteria for their further use. While a ZIKV glycoprotein E homology model was initially described in the immature conformation as a trimer, we now describe the mature dimer conformer which allowed the construction of an illustration of the complete virion. By comparing illustrations of ZIKV based on this new homology model and the dengue virus crystal structure we propose potential differences that could be exploited for antiviral and vaccine design. The prediction of sites for glycosylation on this protein may also be useful in this regard. While we await a cryo-EM structure of ZIKV and eventual crystal structures of the individual proteins, these homology models provide the community with a starting point for structure-based design of drugs and vaccines as well as a for computational virtual screening.

scholarly journals Construction and validation of a homology model of the human voltage-gated proton channel hHV1

2013 ◽  
Vol 141 (4) ◽  
pp. 445-465 ◽  
Author(s):  
Kethika Kulleperuma ◽  
Susan M.E. Smith ◽  
Deri Morgan ◽  
Boris Musset ◽  
John Holyoake ◽  
...  
Keyword(s):  
Structural Model ◽  
Proton Translocation ◽  
External Solution ◽  
Homology Model ◽  
Structural Features ◽  
Proton Channel ◽  
Dimensional Structure ◽  
Internal Solution ◽  
Voltage Gated ◽  
Homology Models

The topological similarity of voltage-gated proton channels (HV1s) to the voltage-sensing domain (VSD) of other voltage-gated ion channels raises the central question of whether HV1s have a similar structure. We present the construction and validation of a homology model of the human HV1 (hHV1). Multiple structural alignment was used to construct structural models of the open (proton-conducting) state of hHV1 by exploiting the homology of hHV1 with VSDs of K+ and Na+ channels of known three-dimensional structure. The comparative assessment of structural stability of the homology models and their VSD templates was performed using massively repeated molecular dynamics simulations in which the proteins were allowed to relax from their initial conformation in an explicit membrane mimetic. The analysis of structural deviations from the initial conformation based on up to 125 repeats of 100-ns simulations for each system reveals structural features consistently retained in the homology models and leads to a consensus structural model for hHV1 in which well-defined external and internal salt-bridge networks stabilize the open state. The structural and electrostatic properties of this open-state model are compatible with proton translocation and offer an explanation for the reversal of charge selectivity in neutral mutants of Asp112. Furthermore, these structural properties are consistent with experimental accessibility data, providing a valuable basis for further structural and functional studies of hHV1. Each Arg residue in the S4 helix of hHV1 was replaced by His to test accessibility using Zn2+ as a probe. The two outermost Arg residues in S4 were accessible to external solution, whereas the innermost one was accessible only to the internal solution. Both modeling and experimental data indicate that in the open state, Arg211, the third Arg residue in the S4 helix in hHV1, remains accessible to the internal solution and is located near the charge transfer center, Phe150.

Leading-Edge Film-Cooling Physics: Part II — Heat Transfer Coefficient

2002 ◽  
Author(s):  
William D. York ◽  
James H. Leylek
Keyword(s):  
Heat Transfer ◽  
Experimental Data ◽  
Heat Transfer Coefficient ◽  
Transfer Coefficient ◽  
Film Cooling ◽  
Leading Edge ◽  
Numerical Predictions ◽  
Validation Experiment ◽  
Computational Methodology ◽  
Near Wall

A comprehensive study of film cooling on a turbine airfoil leading edge was performed with a documented, well-tested computational methodology. In this paper, numerically predicted heat transfer coefficients on the film-cooled leading edge are compared with experimental data from the open literature. The results are presented as the ratio of heat transfer coefficient with film cooling to that without film cooling, and the physics behind the surface results are discussed. The leading edge model was a half-cylinder in shape with a bluff afterbody to match the validation experiment, and other geometric parameters matched those of Part I of this study. Coolant at a density equal to that of the mainstream flow was injected through three rows of cylindrical film-cooling holes. One row of holes was centered on the stagnation line of the cylinder, and the other two rows were located ±3.5 hole diameters off stagnation. The downstream rows were staggered such that they were centered laterally between holes in the stagnation row. The holes were inclined at 20° with the surface, and made a 90° angle with the streamwise direction (radial injection). Four average blowing ratios were simulated in the range of 0.75 to 1.9, corresponding to the same momentum flux ratios as in Part I of this work. The multi-block, unstructured numerical grid was characterized by high quality and density, especially in the near wall region, in order to minimize error in predictions of the heat transfer. A fully-implicit scheme was used to solve the steady Reynolds-averaged Navier-Stokes equations, and a realizable k-ε model provided turbulence closure. A two-layer near-wall treatment allowed the resolution of the viscous sublayer for maximum accuracy in the prediction of the wall heat transfer coefficient. The numerical predictions exhibited generally good agreement with experimental data. The heat transfer coefficient was observed to increase sharply aft of the holes in the downstream rows. When coupled with the adiabatic effectiveness results of the first paper in this series, it is evident that a systematic computational methodology may be effectively applied to investigate and understand the complicated leading edge film-cooling problem.

scholarly journals BIO-GATS: A Tool for Automated GPCR Template Selection Through a Biophysical Approach for Homology Modeling

2021 ◽  
Vol 8 ◽  
Author(s):  
Amara Jabeen ◽  
Ramya Vijayram ◽  
Shoba Ranganathan
Keyword(s):  
Data Bank ◽  
Binding Pocket ◽  
The United States ◽  
Sequence Identity ◽  
United States Food ◽  
Biophysical Approach ◽  
States Food ◽  
Template Selection ◽  
Approved Drugs ◽  
Homology Models

G protein-coupled receptors (GPCRs) are the largest family of membrane proteins with more than 800 members. GPCRs are involved in numerous physiological functions within the human body and are the target of more than 30% of the United States Food and Drug Administration (FDA) approved drugs. At present, over 400 experimental GPCR structures are available in the Protein Data Bank (PDB) representing 76 unique receptors. The absence of an experimental structure for the majority of GPCRs demand homology models for structure-based drug discovery workflows. The generation of good homology models requires appropriate templates. The commonly used methods for template selection are based on sequence identity. However, there exists low sequence identity among the GPCRs. Sequences with similar patterns of hydrophobic residues are often structural homologs, even with low sequence identity. Extending this, we propose a biophysical approach for template selection based principally on hydrophobicity correspondence between the target and the template. Our approach takes into consideration other relevant parameters, including resolution, similarity within the orthosteric binding pocket of GPCRs, and structure completeness, for template selection. The proposed method was implemented in the form of a free tool called Bio-GATS, to provide the user with easy selection of the appropriate template for a query GPCR sequence. Bio-GATS was successfully validated with recent published benchmarking datasets. An application to an olfactory receptor to select an appropriate template has also been provided as a case study.

scholarly journals Experimental accuracy in protein structure refinement via molecular dynamics simulations

2018 ◽  
Vol 115 (52) ◽  
pp. 13276-13281 ◽  
Author(s):  
Lim Heo ◽  
Michael Feig
Keyword(s):  
Molecular Dynamics ◽  
Protein Structure ◽  
Structure Prediction ◽  
Structure Refinement ◽  
Energy Landscape ◽  
Md Simulations ◽  
Homology Model ◽  
Experimental Accuracy ◽  
Markov State Modeling ◽  
Homology Models

Refinement is the last step in protein structure prediction pipelines to convert approximate homology models to experimental accuracy. Protocols based on molecular dynamics (MD) simulations have shown promise, but current methods are limited to moderate levels of consistent refinement. To explore the energy landscape between homology models and native structures and analyze the challenges of MD-based refinement, eight test cases were studied via extensive simulations followed by Markov state modeling. In all cases, native states were found very close to the experimental structures and at the lowest free energies, but refinement was hindered by a rough energy landscape. Transitions from the homology model to the native states require the crossing of significant kinetic barriers on at least microsecond time scales. A significant energetic driving force toward the native state was lacking until its immediate vicinity, and there was significant sampling of off-pathway states competing for productive refinement. The role of recent force field improvements is discussed and transition paths are analyzed in detail to inform which key transitions have to be overcome to achieve successful refinement.

Coupling an Ensemble of Homologues Improves Refinement of Protein Homology Models

2015 ◽  
Vol 11 (12) ◽  
pp. 5578-5582 ◽  
Author(s):  
André Wildberg ◽  
Dennis Della Corte ◽  
Gunnar F. Schröder
Keyword(s):  
Protein Homology ◽  
Homology Models

scholarly journals Relative Binding Free Energy Calculations Applied to Protein Homology Models

2016 ◽  
Vol 56 (12) ◽  
pp. 2388-2400 ◽  
Author(s):  
Daniel Cappel ◽  
Michelle Lynn Hall ◽  
Eelke B. Lenselink ◽  
Thijs Beuming ◽  
Jun Qi ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Protein Homology ◽  
Energy Calculations ◽  
Relative Binding ◽  
Binding Free Energy Calculations ◽  
Homology Models

scholarly journals Illustrating and homology modeling the proteins of the Zika virus

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 275 ◽  
Author(s):  
Sean Ekins ◽  
John Liebler ◽  
Bruno J. Neves ◽  
Warren G. Lewis ◽  
Megan Coffee ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Crystal Structures ◽  
Zika Virus ◽  
Antiviral Drug ◽  
Homology Model ◽  
Glycoprotein E ◽  
Starting Point ◽  
Homology Models

The Zika virus (ZIKV) is a flavivirus of the familyFlaviviridae, which is similar to dengue virus, yellow fever and West Nile virus. Recent outbreaks in South America, Latin America, the Caribbean and in particular Brazil have led to concern for the spread of the disease and potential to cause Guillain-Barré syndrome and microcephaly. Although ZIKV has been known of for over 60 years there is very little in the way of knowledge of the virus with few publications and no crystal structures. No antivirals have been tested against it eitherin vitroorin vivo. ZIKV therefore epitomizes a neglected disease. Several suggested steps have been proposed which could be taken to initiate ZIKV antiviral drug discovery using both high throughput screens as well as structure-based design based on homology models for the key proteins. We now describe preliminary homology models created for NS5, FtsJ, NS4B, NS4A, HELICc, DEXDc, peptidase S7, NS2B, NS2A, NS1, E stem, glycoprotein M, propeptide, capsid and glycoprotein E using SWISS-MODEL. Eleven out of 15 models pass our criteria for selection. While a ZIKV glycoprotein E homology model was initially described in the immature conformation as a trimer, we now describe the mature dimer conformer which allowed the construction of an illustration of the complete virion. By comparing illustrations of ZIKV based on this new homology model and the dengue virus crystal structure we propose potential differences that could be exploited for antiviral and vaccine design. The prediction of sites for glycosylation on this protein may also be useful in this regard. While we await a cryo-EM structure of ZIKV and eventual crystal structures of the individual proteins, these homology models provide the community with a starting point for structure-based design of drugs and vaccines as well as a for computational virtual screening.

Sign in / Sign up

Export Citation Format

Share Document