☆ 4.8 Article

Understanding ligand-based modulation of the Hsp90 molecular chaperone dynamics at atomic resolution

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2008)

Get Full Text
Add to Collection

Journal

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 23, Pages 7976-7981

Publisher

NATL ACAD SCIENCES
DOI: 10.1073/pnas.0802879105

Keywords

allosteric regulation; binding energy landscapes; protein dynamics; protein folding

Categories

Multidisciplinary Sciences

Ask authors/readers for more resources

Protocol

Community support

Reagent

Community support

Molecular switching and ligand-based modulation of the 90-kDa heat-shock protein (Hsp90) chaperone activity may ultimately facilitate conformational coupling to the ATPase cycle along with activation and recruitment of the broad range of client proteins. We present an atomic resolution analysis of the Hsp90 N-terminal domain (NTD) binding energy landscape by simulating protein dynamics with a range of binding partners. We show that the activity of the molecular chaperone may be linked to (i) local folding-unfolding transitions and conformational switching of the active site lid upon binding and (it) differences in the underlying protein dynamics as a function of the binding partner. This study suggests that structural plasticity of the Hsp90 NTD can be exploited by the molecular chaperone machinery to modulate enhanced structural rigidity during ATP binding and increased protein flexibility as a consequence of the inhibitor binding. The present study agrees with the experimental structural data and provides a plausible molecular model for understanding mechanisms of modulation of molecular chaperone activities by binding partners.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.8
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

Article Biochemistry & Molecular Biology

Conformational Flexibility and Local Frustration in the Functional States of the SARS-CoV-2 Spike B.1.1.7 and B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism of Functional Dynamics and Protein Stability

Gennady Verkhivker

Summary: This study conducted a detailed dynamic and energetic analysis of the SARS-CoV-2 spike protein variants, revealing the effects of mutations on protein conformational changes and stability. The results suggest that mutation-induced energetic frustration can lead to the emergence of multiple conformational states, enhancing the adaptability and transmissibility of the virus. These findings contribute to a better understanding of the mutation mechanisms of SARS-CoV-2.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Add to Collection
Article Biochemistry & Molecular Biology

Allosteric Determinants of the SARS-CoV-2 Spike Protein Binding with Nanobodies: Examining Mechanisms of Mutational Escape and Sensitivity of the Omicron Variant

Gennady Verkhivker

Summary: This study comprehensively analyzed the interaction mechanisms, mutational escape, and sensitivity to the Omicron variant of the SARS-CoV-2 spike protein complexed with nanobodies. The findings suggest that the spike protein can generate escape mutants through specific allosteric hotspots without compromising activity, and the binding affinity and long-range communications of the complexes are controlled by structurally stable regulatory centers and conformationally adaptable hotspots.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2022)

Add to Collection
Article Chemistry, Medicinal

Integrating Protein Interaction Surface Prediction with a Fragment- Based Drug Design: Automatic Design of New Leads with Fragments on Energy Surfaces

Luca Torielli, Stefano A. Serapian, Lara Mussolin, Elisabetta Moroni, Giorgio Colombo

Summary: Protein-protein interactions (PPIs) are important pharmacological targets for developing new therapeutics. This study presents a design strategy that combines the analysis of protein dynamics and energetics with docking and fragment combination to identify substructures involved in PPIs and generate PPI inhibitor candidates. The approach is validated using diverse PPI targets, and the hit molecules share high chemical similarity with experimentally tested inhibitors. This protocol provides a valuable means of generating initial leads against difficult targets for further development and refinement.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2023)

Add to Collection
Article Chemistry, Multidisciplinary

Entropically-Driven Co-assembly of L-Histidine and L-Phenylalanine to Form Supramolecular Materials

Om Shanker Tiwari, Ruth Aizen, Massimiliano Meli, Giorgio Colombo, Linda J. W. Shimon, Noam Tal, Ehud Gazit

Summary: Molecular self- and co-assembly have the ability to form diverse and well-defined supramolecular structures with notable physical properties. By exploring the co-assembly of L-His with different aromatic amino acids, including Phe, Tyr, and Trp, we expanded the structural space of amino acid nanomaterials. The best seamless co-assembly was observed between L-His and L-Phe, resulting in the formation of single crystals.

ACS NANO (2023)

Add to Collection
Review Biochemistry & Molecular Biology

From Deep Mutational Mapping of Allosteric Protein Landscapes to Deep Learning of Allostery and Hidden Allosteric Sites: Zooming in on Allosteric Intersection of Biochemical and Big Data Approaches

Gennady Verkhivker, Mohammed Alshahrani, Grace Gupta, Sian Xiao, Peng Tao

Summary: Recent advances in AI and machine learning have resulted in the development of expert systems and workflows that can model complex chemical and biological phenomena. Machine learning approaches have been used in protein dynamics and allosteric mechanism studies. This review focuses on new developments in allosteric research, specifically in data-intensive biochemical approaches and AI-based computational methods. The review highlights the need for the development of AI-augmented integrative structural biology and emphasizes the importance of an open science infrastructure for machine learning studies of allosteric regulation.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

Add to Collection
Article Biochemistry & Molecular Biology

Novel Allosteric Effectors Targeting Human Transcription Factor TEAD

Mayar Tarek Ibrahim, Gennady. M. M. Verkhivker, Jyoti Misra, Peng Tao

Summary: The Hippo pathway is a conserved signaling network involved in cellular regulatory processes, and the overexpression of YAPs in the Hippo-off state is common in solid tumors. Inhibitors targeting the interaction sites between TEAD and YAP have been developed, and the palmitate-binding pocket in TEAD1-4 proteins is the most effective target. Through experimental screening and chemical modification, six new allosteric inhibitors were identified, and four of them showed enhanced communication between TEAD4 and YAP1 domains.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

Add to Collection
Article Biochemistry & Molecular Biology

Coarse-Grained Molecular Simulations and Ensemble-Based Mutational Profiling of Protein Stability in the Different Functional Forms of the SARS-CoV-2 Spike Trimers: Balancing Stability and Adaptability in BA.1, BA.2 and BA.2.75 Variants

Gennady Verkhivker, Mohammed Alshahrani, Grace Gupta

Summary: This study conducted a systematic comparative analysis of the conformational dynamics, electrostatics, protein stability, and allostery in the spike trimers of different variants. The results indicate that BA.2.75 trimers are the most stable among these variants. Mutational scanning revealed that BA.2.75 trimers are more stable than BA.2 and comparable in stability to the BA.1 variant. Network analysis suggested that the increased stability of the BA.2.75 variant may be linked to the organization and modularity of the residue interaction network.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

Add to Collection
Article Biochemistry & Molecular Biology

Gluten Exorphins Promote Cell Proliferation through the Activation of Mitogenic and Pro-Survival Pathways

Federico Manai, Lisa Zanoletti, Giulia Morra, Samman Mansoor, Francesca Carriero, Elena Bozzola, Stella Muscianisi, Sergio Comincini

Summary: Celiac disease is an autoimmune disorder that affects the small intestine. It is caused by the ingestion of gluten, a storage protein found in wheat, barley, rye, and related cereals. Gluten exorphins (GEs), a group of biologically active peptides, have been proposed to contribute to asymptomatic CD.

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES (2023)

Add to Collection
Review Chemistry, Medicinal

Exploring and Learning the Universe of Protein Allostery Using Artificial Intelligence Augmented Biophysical and Computational Approaches

Steve Agajanian, Mohammed Alshahrani, Fang Bai, Peng Tao, Gennady M. Verkhivker

Summary: Allosteric mechanisms play a crucial role in regulating complex biochemical processes and communication in cells. Understanding and characterizing these mechanisms require innovative computational and experimental approaches, empowered by artificial intelligence technologies, to obtain detailed knowledge of allosteric states and interactions. Recent developments in deep mutational scanning, structural prediction methods, machine learning, and structural biology have provided new insights into allosteric protein functions and their implications in viral infection.

JOURNAL OF CHEMICAL INFORMATION AND MODELING (2023)

Add to Collection
Article Virology

Balancing Functional Tradeoffs between Protein Stability and ACE2 Binding in the SARS-CoV-2 Omicron BA.2, BA.2.75 and XBB Lineages: Dynamics-Based Network Models Reveal Epistatic Effects Modulating Compensatory Dynamic and Energetic Changes

Gennady Verkhivker, Mohammed Alshahrani, Grace Gupta

Summary: In this study, the conformational dynamics, structural stability, and binding affinities of the SARS-CoV-2 Spike Omicron complexes with the host receptor ACE2 were systematically characterized. The results showed that stability hotspots and spatially localized Omicron binding affinity centers drive the increased stability and enhanced binding affinity of certain variants. A network-based community model revealed the role of binding hotspots in mediating epistatic couplings, and the F486 mutation was found to modulate local interactions and rewire the global network of local communities, restoring both stability and binding affinity of a specific variant.

VIRUSES-BASEL (2023)

Add to Collection
Editorial Material Chemistry, Multidisciplinary

Editorial: Computational drug discovery for targeting of protein-protein interfaces -Volume II

Giulia Morra, Massimiliano Meli, Elisabetta Moroni, Alessandro Pandini

FRONTIERS IN CHEMISTRY (2023)

Add to Collection
Review Chemistry, Physical

Computational Methods in Immunology and Vaccinology: Design and Development of Antibodies and Immunogens

Federica Guarra, Giorgio Colombo

Summary: The design of new biomolecules that utilize immune mechanisms for disease treatment is a major challenge for computational and simulative approaches. Antibodies have emerged as an important class of therapeutics, particularly in cancer treatment and other diseases. This article provides a summary of the state-of-the-art computational approaches for designing antibodies and antigens, as well as key methodologies for identifying epitopes for B-cell and T-cell responses. The focus is on structure- and physics-based models, which are favored over purely sequence-based approaches. The implications of novel methods in engineering biomolecules with tailor-made immunological properties for therapeutic purposes are discussed. In addition, the integration of structure- and physics-based methods with emerging Artificial Intelligence technologies for predicting and designing novel antigens, epitopes, and antibodies presents extraordinary challenges and opportunities.

JOURNAL OF CHEMICAL THEORY AND COMPUTATION (2023)

Add to Collection
Article Virology

Exploring Conformational Landscapes and Cryptic Binding Pockets in Distinct Functional States of the SARS-CoV-2 Omicron BA.1 and BA.2 Trimers: Mutation-Induced Modulation of Protein Dynamics and Network-Guided Prediction of Variant-Specific Allosteric Binding Sites

Gennady Verkhivker, Mohammed Alshahrani, Grace Gupta

Summary: This study explores the conformation and binding pockets of the spike protein of SARS-CoV-2 Omicron variants, revealing differences between the BA.1 and BA.2 variants and the critical role of conformational plasticity in modulating the distribution of binding sites. The results provide significant insights into the dynamic and network features of available binding pockets in spike proteins and offer a new opportunity for therapeutic interventions for Omicron variants.

VIRUSES-BASEL (2023)

Add to Collection
Article Chemistry, Physical

Probing conformational landscapes of binding and allostery in the SARS-CoV-2 omicron variant complexes using microsecond atomistic simulations and perturbation-based profiling approaches: hidden role of omicron mutations as modulators of allosteric signaling and epistatic relationships

Gennady Verkhivker, Mohammed Alshahrani, Grace Gupta, Sian Xiao, Peng Tao

Summary: In this study, the conformational dynamics, binding, and allosteric communications in the Omicron spike protein complexes with the ACE2 host receptor were examined using molecular dynamics simulations and perturbation-based network profiling approaches. The findings revealed the conformational landscapes of the Omicron variants and their impact on protein stability and binding affinity. Moreover, the study elucidated the role of specific mutation hotspots in Omicron variants in regulating allostery and signaling in the complexes. Overall, the study provides a comprehensive analysis of the effects of Omicron mutations on thermodynamics, binding, and allosteric signaling in the complexes with ACE2 receptor.

PHYSICAL CHEMISTRY CHEMICAL PHYSICS (2023)

Add to Collection
No Data Available
Webinars Posters Questions Hubs Funding Journals Papers Connect Collections Reviewers About Us FAQs Mobile App Privacy Policy Terms of Use
© Peeref 2019-2024. All rights reserved.