Abstract
In reported microcanonical molecular dynamics simulations, fast-folding proteins CLN025 and Trp-cage autonomously folded to experimentally determined native conformations. However, the folding times of these proteins derived from the simulations were more than 4–10 times longer than their experimental values. This article reports autonomous folding of CLN025 and Trp-cage in isobaric–isothermal molecular dynamics simulations with agreements within factors of 0.69–1.75 between simulated and experimental folding times at different temperatures. These results show that CLN025 and Trp-cage can now autonomously fold in silico as fast as in experiments, and suggest that the accuracy of folding simulations for fast-folding proteins begins to overlap with the accuracy of folding experiments. This opens new prospects of developing computer algorithms that can predict both ensembles of conformations and their interconversion rates for a protein from its sequence for artificial intelligence on how and when a protein acts as a receiver, switch, and relay to facilitate various subcellular-to-tissue communications. Then the genetic information that encodes proteins can be better read in the context of intricate biological functions.
Highlights
How fast can fast-folding proteins autonomously fold in silico? This question is important because experimental folding times [1,2,3] are rigorous benchmarks for evaluating the accuracy of protein folding simulations
Simulated folding times of β-protein CLN025 at different temperatures To determine how fast β-protein CLN025 autonomously folds in silico, 40 distinct, independent, unrestricted, unbiased, and isobaric–isothermal, and 3.16-μs molecular dynamics (MD) simulations of CLN025 were performed at 300 K
Using (i) the average conformation of the largest cluster as the predicted native conformation of CLN025 and (ii) CαβRMSD of ≤0.98 Å from the predicted native conformation to define the native structural ensemble of CLN025, the first time-instant at which CαβRMSD of the fulllength CLN025 sequence reached ≤0.98 Å was recorded as an individual folding time for each of the 40 simulations (Table S3A)
Summary
How fast can fast-folding proteins autonomously fold in silico? This question is important because experimental folding times (τs) [1,2,3] are rigorous benchmarks for evaluating the accuracy of protein folding simulations. [16,18], one advantage of this survival analysis method is that the τ prediction does assume that the fast-folding protein must follow a two-state folding mechanism; another advantage is rigorous estimation of mean τ and 95%CI from ≥20 simulations that are relatively short so that a few of these simulations may not capture a folding event.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Biochemical and Biophysical Research Communications
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
