scholarly journals Understanding the Binding Transition State After the Conformational Selection Step: The Second Half of the Molecular Recognition Process Between NS1 of the 1918 Influenza Virus and Host p85β

2021 ◽  
Vol 8 ◽  
Author(s):  
Alyssa Dubrow ◽  
Iktae Kim ◽  
Elias Topo ◽  
Jae-Hyun Cho
Keyword(s):  
Free Energy ◽  
Molecular Recognition ◽  
Transition State ◽  
Hydrophobic Interactions ◽  
Nonstructural Protein ◽  
Conformational Dynamics ◽  
Linear Free Energy Relationship ◽  
Conformational Selection ◽  
Nonstructural Protein 1 ◽  
1918 Influenza

Biomolecular recognition often involves conformational changes as a prerequisite for binding (i.e., conformational selection) or concurrently with binding (i.e., induced-fit). Recent advances in structural and kinetic approaches have enabled the detailed characterization of protein motions at atomic resolution. However, to fully understand the role of the conformational dynamics in molecular recognition, studies on the binding transition state are needed. Here, we investigate the binding transition state between nonstructural protein 1 (NS1) of the pandemic 1918 influenza A virus and the human p85β subunit of PI3K. 1918 NS1 binds to p85β via conformational selection. We present the free-energy mapping of the transition and bound states of the 1918 NS1:p85β interaction using linear free energy relationship and ϕ-value analyses. We find that the binding transition state of 1918 NS1 and p85β is structurally similar to the bound state with well-defined binding orientation and hydrophobic interactions. Our finding provides a detailed view of how protein motion contributes to the development of intermolecular interactions along the binding reaction coordinate.

scholarly journals Molecular recognition of a host protein by NS1 of pandemic and seasonal influenza A viruses

2020 ◽  
Vol 117 (12) ◽  
pp. 6550-6558 ◽  
Author(s):  
Jae-Hyun Cho ◽  
Baoyu Zhao ◽  
Jie Shi ◽  
Nowlan Savage ◽  
Qingliang Shen ◽  
...  
Keyword(s):  
Molecular Recognition ◽  
Influenza A ◽  
Nonstructural Protein ◽  
Conformational Dynamics ◽  
Relaxation Dispersion ◽  
Binding Kinetics ◽  
Host Protein ◽  
Dynamics Simulation ◽  
Nonstructural Protein 1 ◽  
Strain Dependent

The 1918 influenza A virus (IAV) caused the most severe flu pandemic in recorded human history. Nonstructural protein 1 (NS1) is an important virulence factor of the 1918 IAV. NS1 antagonizes host defense mechanisms through interactions with multiple host factors. One pathway by which NS1 increases virulence is through the activation of phosphoinositide 3-kinase (PI3K) by binding to its p85β subunit. Here we present the mechanism underlying the molecular recognition of the p85β subunit by 1918 NS1. Using X-ray crystallography, we determine the structure of 1918 NS1 complexed with p85β of human PI3K. We find that the 1918 NS1 effector domain (1918 NS1ED) undergoes a conformational change to bind p85β. Using NMR relaxation dispersion and molecular dynamics simulation, we identify that free 1918 NS1EDexists in a dynamic equilibrium between p85β-binding–competent and –incompetent conformations in the submillisecond timescale. Moreover, we discover that NS1EDproteins of 1918 (H1N1) and Udorn (H3N2) strains exhibit drastically different conformational dynamics and binding kinetics to p85β. These results provide evidence of strain-dependent conformational dynamics of NS1. Using kinetic modeling based on the experimental data, we demonstrate that 1918 NS1EDcan result in the faster hijacking of p85β compared to Ud NS1ED, although the former has a lower affinity to p85β than the latter. Our results suggest that the difference in binding kinetics may impact the competition with cellular antiviral responses for the activation of PI3K. We anticipate that our findings will increase the understanding of the strain-dependent behaviors of influenza NS1 proteins.

scholarly journals Catalysis: transition-state molecular recognition?

2010 ◽  
Vol 6 ◽  
pp. 1026-1034 ◽  
Author(s):  
Ian H Williams
Keyword(s):  
Free Energy ◽  
Molecular Recognition ◽  
Transition State ◽  
Computational Modelling ◽  
Catalytic Antibodies ◽  
Single Atom ◽  
Boat Conformation ◽  
Methyl Transferase ◽  
Modelling Studies ◽  
Dynamics Simulations

The key to understanding the fundamental processes of catalysis is the transition state (TS): indeed, catalysis is a transition-state molecular recognition event. Practical objectives, such as the design of TS analogues as potential drugs, or the design of synthetic catalysts (including catalytic antibodies), require prior knowledge of the TS structure to be mimicked. Examples, both old and new, of computational modelling studies are discussed, which illustrate this fundamental concept. It is shown that reactant binding is intrinsically inhibitory, and that attempts to design catalysts that focus simply upon attractive interactions in a binding site may fail. Free-energy changes along the reaction coordinate for SN2 methyl transfer catalysed by the enzyme catechol-O-methyl transferase are described and compared with those for a model reaction in water, as computed by hybrid quantum-mechanical/molecular-mechanical molecular dynamics simulations. The case is discussed of molecular recognition in a xylanase enzyme that stabilises its sugar substrate in a (normally unfavourable) boat conformation and in which a single-atom mutation affects the free-energy of activation dramatically.

Linear free energy relationship and kinetic isotope effects as measures for the transition-state variation — A case of the neophyl system

2005 ◽  
Vol 83 (9) ◽  
pp. 1606-1614 ◽  
Author(s):  
Salai Cheettu Ammal ◽  
Hiroshi Yamataka
Keyword(s):  
Free Energy ◽  
Transition State ◽  
Density Functional ◽  
Isotope Effects ◽  
Kinetic Isotope Effects ◽  
Single Step ◽  
Linear Free Energy Relationship ◽  
Linear Free Energy ◽  
Kinetic Isotope ◽  
State Variation

Ab initio calculations at the MP2/6-31G* level and density functional theory (B3LYP/6-311+G**) calculations have been performed on acid-catalyzed ionizations of substituted neophyl alcohols to investigate whether a variation of the transition-state (TS) structure is reflected in the kinetic isotope effects (KIE) and linear free energy relationship. The effect of substituents on KIEs, TS structures, and activation and reaction energies was calculated. This study revealed that a curved Brønsted-type plot could arise for a single-step process from the variation of TS structure with the substituent, whereas the Hammett plots with a dual-parameter treatment can not detect such TS variation. The variation of KIEs at various positions of neophyl alcohol reflects the variation of TS structures in a manner consistent with the More O'Ferrall – Jencks type reaction diagram analyses.Key words: transition-state variation, substituent effect, kinetic isotope effect, linear free energy relationship.

scholarly journals Discovery of Natural Phenol Catechin as a Multitargeted Agent Against SARS-CoV-2 For the Plausible Therapy of COVID-19

2020 ◽  
Author(s):  
Chandra Bhushan Mishra ◽  
Preeti Pandey ◽  
Ravi Datta Sharma ◽  
Raj Kumar Mongre ◽  
Andrew M Lynn ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Interactions ◽  
Nucleocapsid Protein ◽  
Rational Design ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Nonstructural Protein ◽  
Cathepsin L ◽  
Target Proteins ◽  
Drug Molecules

The global pandemic crisis, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed the lives of millions of people across the world. Development and testing of anti-SARS-CoV-2 drugs or vaccines, are not turned to be realistic in the timeframe needed to combat this pandemic. Thus, rigorous efforts are still ongoing for the drug repurposing as a clinical treatment strategy to control COVID-19. Here we report a comprehensive computational approach to identify the multi-targeted drug molecules against the SARS-CoV-2 proteins, which are crucially involved in the viral-host interaction, replication of the virus inside the host, disease progression and transmission of coronavirus infection. Virtual screening of 72 FDA approved potential antiviral drugs against the target proteins: Spike (S) glycoprotein, human angiotensin-converting enzyme 2 (hACE2), 3-chymotrypsin-like cysteine protease (3CLpro), Cathepsin L, Nucleocapsid protein, RNA-dependent RNA polymerase (RdRp) and nonstructural protein 6 (NSP6) resulted in the selection of seven drugs which preferentially binds to the target proteins. Further, the molecular interactions determined by MD simulation, free energy landscape and the binding free energy estimation, using MM-PBSA revealed that among 72 drug molecules, catechin (flavan-3-ol) can effectively bind to 3CLpro, Cathepsin L, RBD of S protein, NSP-6, and Nucleocapsid protein. It is more conveniently involved in key molecular interactions, showing binding free energy (ΔGbind) in the range of -5.09 kcal/mol (Cathepsin L) to -26.09 kcal/mol (NSP6). At the binding pocket, catechin is majorly stabilized by the hydrophobic interactions, displays ΔEvdW values -7.59 to -37.39 kcal/mol. Thus, the structural insights of better binding affinity and favourable molecular interaction of catechin towards multiple target proteins, signifies that catechin can be potentially explored as a multitargeted agent in the rational design of effective therapies against COVID-19.<br>

scholarly journals Discovery of Natural Phenol Catechin as a Multitargeted Agent Against SARS-CoV-2 For the Plausible Therapy of COVID-19

2020 ◽  
Author(s):  
Chandra Bhushan Mishra ◽  
Preeti Pandey ◽  
Ravi Datta Sharma ◽  
Raj Kumar Mongre ◽  
Andrew M Lynn ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Interactions ◽  
Nucleocapsid Protein ◽  
Rational Design ◽  
Hydrophobic Interactions ◽  
Binding Free Energy ◽  
Nonstructural Protein ◽  
Cathepsin L ◽  
Target Proteins ◽  
Drug Molecules

The global pandemic crisis, COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has claimed the lives of millions of people across the world. Development and testing of anti-SARS-CoV-2 drugs or vaccines, are not turned to be realistic in the timeframe needed to combat this pandemic. Thus, rigorous efforts are still ongoing for the drug repurposing as a clinical treatment strategy to control COVID-19. Here we report a comprehensive computational approach to identify the multi-targeted drug molecules against the SARS-CoV-2 proteins, which are crucially involved in the viral-host interaction, replication of the virus inside the host, disease progression and transmission of coronavirus infection. Virtual screening of 72 FDA approved potential antiviral drugs against the target proteins: Spike (S) glycoprotein, human angiotensin-converting enzyme 2 (hACE2), 3-chymotrypsin-like cysteine protease (3CLpro), Cathepsin L, Nucleocapsid protein, RNA-dependent RNA polymerase (RdRp) and nonstructural protein 6 (NSP6) resulted in the selection of seven drugs which preferentially binds to the target proteins. Further, the molecular interactions determined by MD simulation, free energy landscape and the binding free energy estimation, using MM-PBSA revealed that among 72 drug molecules, catechin (flavan-3-ol) can effectively bind to 3CLpro, Cathepsin L, RBD of S protein, NSP-6, and Nucleocapsid protein. It is more conveniently involved in key molecular interactions, showing binding free energy (ΔGbind) in the range of -5.09 kcal/mol (Cathepsin L) to -26.09 kcal/mol (NSP6). At the binding pocket, catechin is majorly stabilized by the hydrophobic interactions, displays ΔEvdW values -7.59 to -37.39 kcal/mol. Thus, the structural insights of better binding affinity and favourable molecular interaction of catechin towards multiple target proteins, signifies that catechin can be potentially explored as a multitargeted agent in the rational design of effective therapies against COVID-19.<br>

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