The Role of Transient Intermediate Structures in the Unfolding of the Trp-Cage Fast-Folding Protein: Generating Ensembles from Time-Resolved X-ray Solution Scattering with Genetic Algorithms.
Arnold M ChanAdam K NijhawanDarren J HsuDenis LeshchevDolev RimmermanIrina KoshelevaKevin L KohlstedtLin X ChenPublished in: The journal of physical chemistry letters (2023)
The Trp-cage miniprotein is one of the smallest systems to exhibit a stable secondary structure and fast-folding dynamics, serving as an apt model system to study transient intermediates with both experimental and computational analyses. Previous spectroscopic characterizations that have been done on Trp-cage have inferred a single stable intermediate on a pathway from folded to unfolded basins. We aim to bridge the understanding of Trp-cage structural folding dynamics on microsecond-time scales, by utilizing time-resolved X-ray solution scattering to probe the temperature-induced unfolding pathway. Our results indicate the formation of a conformationally extended intermediate on the time scale of 1 μs, which undergoes complete unfolding within 5 μs. We further investigated the atomistic structural details of the unfolding pathway using a genetic algorithm to generate ensemble model fits to the scattering profiles. This analysis paves the way for direct benchmarking of theoretical models of protein folding ensembles produced with molecular dynamics simulations.
Keyphrases
- molecular dynamics simulations
- molecular docking
- high resolution
- machine learning
- single molecule
- genome wide
- cerebral ischemia
- copy number
- protein protein
- dual energy
- diabetic rats
- magnetic resonance imaging
- computed tomography
- dna methylation
- oxidative stress
- neural network
- living cells
- drug induced
- subarachnoid hemorrhage
- data analysis