Protein–Protein Interactions Affect Alpha Helix Stability in Crowded Environments

2015 ◽  
Vol 119 (7) ◽  
pp. 2956-2967 ◽  
Author(s):  
Bryanne Macdonald ◽  
Shannon McCarley ◽  
Sundus Noeen ◽  
Alan E. van Giessen
Keyword(s):  
Protein Interactions ◽  
Alpha Helix ◽  
Protein Protein Interactions ◽  
Helix Stability ◽  
Crowded Environments

scholarly journals Protein-Protein Interactions Affect Native State Stability in Crowded Environments

2015 ◽  
Vol 108 (2) ◽  
pp. 52a
Author(s):  
Alan E. van Giessen ◽  
Bryanne Macdonald ◽  
Shannon McCarley ◽  
Sundus Noeen ◽  
Rabeb Layouni
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Native State ◽  
Crowded Environments

ChemInform Abstract: Design and Synthesis of Thienylpyridyl Garlands as Non-Peptidic Alpha Helix Mimetics and Potential Protein-Protein Interactions Disruptors.

ChemInform ◽  
2011 ◽  
Vol 42 (52) ◽  
pp. no-no
Author(s):  
Marcella De Giorgi ◽  
Anne Sophie Voisin-Chiret ◽  
Jana Sopkova-de Oliveira Santos ◽  
Filomena Corbo ◽  
Carlo Franchini ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Alpha Helix ◽  
Protein Protein Interactions ◽  
Design And Synthesis ◽  
Helix Mimetics

scholarly journals Computational and experimental studies of plasmodium falciparum protein PfAMA1 domain-II loop dynamics: implications in PfAMA1-PfRON2 binding event

2021 ◽  
Author(s):  
Suman Sinha ◽  
Anamika Biswas ◽  
Jagannath Mondal ◽  
Kalyaneswar Mandal
Keyword(s):  
Drug Discovery ◽  
Protein Interactions ◽  
Experimental Studies ◽  
Alpha Helix ◽  
Dynamics Simulation ◽  
Malarial Parasite ◽  
Titration Calorimetry ◽  
Protein Protein Interactions ◽  
Human Red Blood Cells ◽  
Developed Nations

Protein-protein interactions are interesting targets for various drug discovery campaigns. One such promising and therapeutically pertinent protein-protein complex is PfAMA1-PfRON2, which is involved in malarial parasite invasion into human red blood cells. A thorough understanding of the interactions between these macromolecular binding partners is absolutely necessary to design better therapeutics to fight against the age-old disease affecting mostly under-developed nations. Although crystal structures of several PfAMA1-PfRON2 complexes have been solved to understand the molecular interactions between these two proteins, the mechanistic aspects of the domain II loop-PfRON2 association is far from clear. The current work investigates a crucial part of the recognition event; i.e., how the domain II loop of PfAMA1 exerts its effect on the alpha helix of the PfRON2, thus influencing the overall kinetics of this intricate recognition phenomenon. To this end, we have conducted thorough computational investigation of the dynamics and free energetics of domain II loop closing processes using molecular dynamics simulation. The computational results are validated by systematic alanine substitutions of the PfRON2 peptide helix. The subsequent evaluation of the binding affinity of Ala-substituted PfRON2 peptide ligands by surface plasmon resonance (SPR) and isothermal titration calorimetry (ITC) provides a rank of the relative importance of the residues in context. Our combined (computational and experimental) investigation has revealed that the domain II loop of PfAMA1 is in fact responsible for arresting the PfRON2 molecule from egress, K2027 and D2028 of PfRON2 being the determinant residues for the capturing event. Our study provides a comprehensive understanding of the molecular recognition event between PfAMA1 and PfRON2, specifically in the post binding stage, which potentially can be utilized for drug discovery against malaria.

scholarly journals Characterizing alpha helical properties of Ebola viral proteins as potential targets for inhibition of alpha-helix mediated protein-protein interactions

F1000Research ◽  
2015 ◽  
Vol 3 ◽  
pp. 251 ◽  
Author(s):  
Sandeep Chakraborty ◽  
Basuthkar J. Rao ◽  
Bjarni Asgeirsson ◽  
Abhaya M. Dandekar
Keyword(s):  
West Africa ◽  
Protein Interactions ◽  
Rational Design ◽  
Ebola Virus ◽  
Structural Alignment ◽  
Alpha Helix ◽  
Neutralizing Antibody ◽  
Protein Protein Interactions ◽  
Host Proteins ◽  
Alpha Helices

Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The neutralizing antibody (KZ52) derived from a human survivor of the 1995 Kikwit outbreak recognizes a protein epitope on this AH, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such `hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the `largest Ebola epidemic, affecting multiple countries in West Africa' (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html).

scholarly journals Synthesis of a Bcl9 Alpha-Helix Mimetic for Inhibition of PPIs by a Combination of Electrooxidative Phenol Coupling and Pd-Catalyzed Cross Coupling

Catalysts ◽  
2020 ◽  
Vol 10 (3) ◽  
pp. 340 ◽  
Author(s):  
Martin Vareka ◽  
Benedikt Dahms ◽  
Mario Lang ◽  
Minh Hao Hoang ◽  
Melanie Trobe ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Alpha Helix ◽  
Cross Coupling ◽  
Coupling Reactions ◽  
Protein Protein Interactions ◽  
Interaction Sites ◽  
Cross Coupling Reactions ◽  
Helix Mimetics ◽  
Leaving Groups ◽  
Metal Catalyzed

Teraryl-based alpha-helix mimetics have resulted in efficient inhibitors of protein-protein interactions (PPIs). Extending the concept to even longer oligoarene systems would allow for the mimicking of even larger interaction sites. We present a highly efficient synthetic modular access to quateraryl alpha-helix mimetics, in which, at first, two phenols undergo electrooxidative dehydrogenative cross-coupling. The resulting 4,4′-biphenol is then activated by conversion to nonaflates, which serve as leaving groups for iterative Pd-catalyzed Suzuki-cross-coupling reactions with suitably substituted pyridine boronic acids. This work, for the first time, demonstrates the synthetic efficiency of using both electroorganic as well as transition-metal catalyzed cross-coupling in the assembly of oligoarene structures.

scholarly journals Quantifying Protein-Protein Interactions in Molecular Simulations

2019 ◽  
Author(s):  
Alfredo Jost Lopez ◽  
Patrick K. Quoika ◽  
Max Linke ◽  
Gerhard Hummer ◽  
Juergen Koefinger
Keyword(s):  
Molecular Dynamics ◽  
Protein Interactions ◽  
Virial Coefficient ◽  
Analytical Ultracentrifugation ◽  
Molecular Simulations ◽  
Simple Expression ◽  
Protein Protein Interactions ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Crowded Environments

<p><a></a></p><p><a></a>We present simple, accurate, and efficient methods to estimate the dissociation constant K<sub>d </sub>and the second osmotic virial coefficient B<sub>2 </sub>from molecular simulations. We show that for simulations of two proteins in a box, K<sub>d </sub>is determined by B<sub>2 </sub>and the fraction of bound protein. We present two different methods to calculate B<sub>2 </sub>from Monte Carlo and molecular dynamics simulations using implicit or explicit solvent. We derive a surprisingly simple expression for B<sub>2</sub>, adding significantly to the understanding of this important quantity. Non-binding interactions of proteins and other macromolecules shape the physicochemical properties of the crowded environments inside cells and of biomolecular condensates. We show how to extract the contributions of non-binding conformations to B<sub>2 </sub>and discuss how these can be determined in analytical ultracentrifugation and SAXS experiments. We expect that our methods will prove to be instrumental in force parameterization efforts and high-throughput studies of large interactomes. </p>

scholarly journals Quantifying Protein-Protein Interactions in Molecular Simulations

2019 ◽  
Author(s):  
Alfredo Jost Lopez ◽  
Patrick K. Quoika ◽  
Max Linke ◽  
Gerhard Hummer ◽  
Juergen Koefinger
Keyword(s):  
Molecular Dynamics ◽  
Protein Interactions ◽  
Virial Coefficient ◽  
Analytical Ultracentrifugation ◽  
Molecular Simulations ◽  
Simple Expression ◽  
Protein Protein Interactions ◽  
Explicit Solvent ◽  
Dynamics Simulations ◽  
Crowded Environments

<p><a></a></p><p><a></a>We present simple, accurate, and efficient methods to estimate the dissociation constant K<sub>d </sub>and the second osmotic virial coefficient B<sub>2 </sub>from molecular simulations. We show that for simulations of two proteins in a box, K<sub>d </sub>is determined by B<sub>2 </sub>and the fraction of bound protein. We present two different methods to calculate B<sub>2 </sub>from Monte Carlo and molecular dynamics simulations using implicit or explicit solvent. We derive a surprisingly simple expression for B<sub>2</sub>, adding significantly to the understanding of this important quantity. Non-binding interactions of proteins and other macromolecules shape the physicochemical properties of the crowded environments inside cells and of biomolecular condensates. We show how to extract the contributions of non-binding conformations to B<sub>2 </sub>and discuss how these can be determined in analytical ultracentrifugation and SAXS experiments. We expect that our methods will prove to be instrumental in force parameterization efforts and high-throughput studies of large interactomes. </p>

scholarly journals Characterizing alpha helical properties of Ebola viral proteins as potential targets for inhibition of alpha-helix mediated protein-protein interactions

F1000Research ◽  
2014 ◽  
Vol 3 ◽  
pp. 251 ◽  
Author(s):  
Sandeep Chakraborty ◽  
Basuthkar J. Rao ◽  
Bjarni Asgeirsson ◽  
Abhaya M. Dandekar
Keyword(s):  
West Africa ◽  
Protein Interactions ◽  
Rational Design ◽  
Ebola Virus ◽  
Structural Alignment ◽  
Alpha Helix ◽  
Neutralizing Antibody ◽  
Protein Protein Interactions ◽  
Host Proteins ◽  
Alpha Helices

Ebola, considered till recently as a rare and endemic disease, has dramatically transformed into a potentially global humanitarian crisis. The genome of Ebola, a member of the Filoviridae family, encodes seven proteins. Based on the recently implemented software (PAGAL) for analyzing the hydrophobicity and amphipathicity properties of alpha helices (AH) in proteins, we characterize the helices in the Ebola proteome. We demonstrate that AHs with characteristically unique features are involved in critical interactions with the host proteins. For example, the Ebola virus membrane fusion subunit, GP2, from the envelope glycoprotein ectodomain has an AH with a large hydrophobic moment. The ability of this AH to bind to other host proteins is disrupted by a neutralizing antibody derived from a human survivor of the 1995 Kikwit outbreak, emphasizing the critical nature of this secondary structure in the virulence of the Ebola virus. Our method ensures a comprehensive list of such `hotspots'. These helices probably are or can be the target of molecules designed to inhibit AH mediated protein-protein interactions. Further, by comparing the AHs in proteins of the related Marburg viruses, we are able to elicit subtle changes in the proteins that might render them ineffective to previously successful drugs. Such differences are difficult to identify by a simple sequence or structural alignment. Thus, analyzing AHs in the small Ebola proteome can aid rational design aimed at countering the `largest Ebola epidemic, affecting multiple countries in West Africa' (http://www.cdc.gov/vhf/ebola/outbreaks/2014-west-africa/index.html).

scholarly journals Effect of protein–protein interactions and solvent viscosity on the rotational diffusion of proteins in crowded environments

2019 ◽  
Vol 21 (2) ◽  
pp. 876-883 ◽  
Author(s):  
Grzegorz Nawrocki ◽  
Alp Karaboga ◽  
Yuji Sugita ◽  
Michael Feig
Keyword(s):  
Protein Interactions ◽  
Rotational Diffusion ◽  
Protein Protein Interactions ◽  
Solvent Viscosity ◽  
Close Proximity ◽  
Crowded Environments

Slow-down of the rotational diffusion of villin in the presence of villin crowder in close proximity.

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