ArticleProceedings of the National Academy of Sciences of the United States of America2013
Free energy landscapes for initiation and branching of protein aggregation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed.
- Inhibitory effect of epigallocatechin-3-gallate as a potent anti-amyloidogenic agent against the G138E mutant of SOD1.Scientific reports · 2026Article
- Biomolecular Condensates as Emerging Biomaterials: Functional Mechanisms and Advances in Computational and Experimental Approaches.Advanced materials (Deerfield Beach, Fla.) · 2025Review
- Structural insights into SOD1: from in silico and molecular dynamics to experimental analyses of ALS-associated E49K and R115G mutants.Frontiers in molecular biosciences · 2025Article
- Inhibitory effect of Fisetin against the aggregation process of SOD1 E100K mutant: computer-based drug design as a potential therapeutic for ALS disease.Frontiers in chemistry · 2025Article
- Exploring the interplay between fibrillization and amorphous aggregation channels on the energy landscapes of tau repeat isoforms.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Competition of individual domain folding with inter-domain interaction in WW domain engineered repeat proteins.Physical chemistry chemical physics : PCCP · 2019Article
- Recent Advances in Computational Protocols Addressing Intrinsically Disordered Proteins.Biomolecules · 2019Review
- Surveying the Energy Landscapes of Aβ Fibril Polymorphism.The journal of physical chemistry. B · 2018Article
- AWSEM-IDP: A Coarse-Grained Force Field for Intrinsically Disordered Proteins.The journal of physical chemistry. B · 2018Article
- Template-Guided Protein Structure Prediction and Refinement Using Optimized Folding Landscape Force Fields.Journal of chemical theory and computation · 2018Article
- Aggregation landscapes of Huntingtin exon 1 protein fragments and the critical repeat length for the onset of Huntington's disease.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- The Aggregation Free Energy Landscapes of Polyglutamine Repeats.Journal of the American Chemical Society · 2016Article
- Exploring the aggregation free energy landscape of the amyloid-β protein (1-40).Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Protein Folding and Structure Prediction from the Ground Up: The Atomistic Associative Memory, Water Mediated, Structure and Energy Model.The journal of physical chemistry. B · 2016Article
- Protein Ensembles: How Does Nature Harness Thermodynamic Fluctuations for Life? The Diverse Functional Roles of Conformational Ensembles in the Cell.Chemical reviews · 2016Review
- Article
- Energy landscapes of a mechanical prion and their implications for the molecular mechanism of long-term memory.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Markov state models of protein misfolding.The Journal of chemical physics · 2016Article
- Sequence- and Temperature-Dependent Properties of Unfolded and Disordered Proteins from Atomistic Simulations.The journal of physical chemistry. B · 2015Article
- Transient misfolding dominates multidomain protein folding.Nature communications · 2015Article
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3 authors.
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Abstract
Experiments on artificial multidomain protein constructs have probed the early stages of aggregation processes, but structural details of the species that initiate aggregation remain elusive. Using the associative-memory, water-mediated, structure and energy model known as AWSEM, a transferable coarse-grained protein model, we performed simulations of fused constructs composed of up to four copies of the Titin I27 domain or its mutant I27* (I59E). Free energy calculations enable us to quantify the conditions under which such multidomain constructs will spontaneously misfold. Consistent with experimental results, the dimer of I27 is found to be the smallest spontaneously misfolding construct. Our results show how structurally distinct misfolded states can be stabilized under different thermodynamic conditions, and this result provides a plausible link between the single-molecule misfolding experiments under native conditions and aggregation experiments under denaturing conditions. The conditions for spontaneous misfolding are determined by the interplay among temperature, effective local protein concentration, and the strength of the interdomain interactions. Above the folding temperature, fusing additional domains to the monomer destabilizes the native state, and the entropically stabilized amyloid-like state is favored. Because it is primarily energetically stabilized, the domain-swapped state is more likely to be important under native conditions. Both protofibril-like and branching structures are found in annealing simulations starting from extended structures, and these structures suggest a possible connection between the existence of multiple amyloidogenic segments in each domain and the formation of branched, amorphous aggregates as opposed to linear fibrillar structures.
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