ArticlePhysical chemistry chemical physics : PCCP2014
The free energy landscape in translational science: how can somatic mutations result in constitutive oncogenic activation?
Article in Physical chemistry chemical physics : PCCP, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- The Evolving Landscape of Protein Allostery: From Computational and Experimental Perspectives.Journal of molecular biology · 2025Review
- Allostery in Disease: Anticancer Drugs, Pockets, and the Tumor Heterogeneity Challenge.Journal of molecular biology · 2025Review
- Pioneer in Molecular Biology: Conformational Ensembles in Molecular Recognition, Allostery, and Cell Function.Journal of molecular biology · 2025Review
- Drug resistance and tumor heterogeneity: cells and ensembles.Biophysical reviews · 2025Review
- Molecular principles underlying aggressive cancers.Signal transduction and targeted therapy · 2025Review
- Hidden water's influence on rhodopsin activation.Biophysical journal · 2024Review
- Allostery: Allosteric Cancer Drivers and Innovative Allosteric Drugs.Journal of molecular biology · 2022Review
- Allostery, and how to define and measure signal transduction.Biophysical chemistry · 2022Review
- Mechanism of activation and the rewired network: New drug design concepts.Medicinal research reviews · 2022Review
- Early stages of misfolding of PAP248-286 at two different pH values: An insight from molecular dynamics simulations.Computational and structural biotechnology journal · 2022Article
- Inhibition of Nonfunctional Ras.Cell chemical biology · 2021Review
- Conformational gating, dynamics and allostery in human monoacylglycerol lipase.Scientific reports · 2020Article
- Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis.Molecules (Basel, Switzerland) · 2020Article
- Leveraging protein dynamics to identify cancer mutational hotspots using 3D structures.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Protein ensembles link genotype to phenotype.PLoS computational biology · 2019Review
- Review: Precision medicine and driver mutations: Computational methods, functional assays and conformational principles for interpreting cancer drivers.PLoS computational biology · 2019Review
- Precision medicine review: rare driver mutations and their biophysical classification.Biophysical reviews · 2019Review
- Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: Combined Study of Molecular Modeling and Dynamic Residue Network Analysis.Molecules (Basel, Switzerland) · 2019Article
- Autoinhibition in Ras effectors Raf, PI3Kα, and RASSF5: a comprehensive review underscoring the challenges in pharmacological intervention.Biophysical reviews · 2018Review
- Conformational landscape of the epidermal growth factor receptor kinase reveals a mutant specific allosteric pocket.Chemical science · 2018Article
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Authors and funding
2 authors.
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Abstract
The free energy landscape theory has transformed the field of protein folding. The significance of perceiving function in terms of conformational heterogeneity is gradually shifting the interest in the community from folding to function. From the free energy landscape standpoint the principles are unchanged: rather than considering the entire protein conformational landscape, the focus is on the ensemble around the bottom of the folding funnel. The protein can be viewed as populating one of two states: active or inactive. The basins of the two states are separated by a surmountable barrier, which allows the conformations to switch between the states. Unless the protein is a repressor, under physiological conditions it typically populates the inactive state. Ligand binding (or post-translational modification) triggers a switch to the active state. Constitutive allosteric mutations work by shifting the population from the inactive to the active state and keeping it there. This can happen by either destabilizing the inactive state, stabilizing the active state, or both. Identification of the mechanism through which they work is important since it may assist in drug discovery. Here we spotlight the usefulness of the free energy landscape in translational science, illustrating how oncogenic mutations can work in key proteins from the EGFR/Ras/Raf/Erk/Mek pathway, the main signaling pathway in cancer. Finally, we delineate the key components which are needed in order to trace the mechanism of allosteric events.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.