A Discard-and-Restart MD algorithm for the sampling of protein intermediate states

We introduce a Discard‑and‑Restart molecular dynamics (MD) algorithm tailored for the sampling of realistic protein intermediate states. It aids computational structure‑based drug discovery by reducing the simulation times to compute a \"quick sketch\" of folding pathways by up to 2000x. The algorithm iteratively performs short MD simulations and measures their proximity to a target state via a collective variable (CV) loss, which can be defined in a flexible fashion, locally or globally.  Using the loss, if the trajectory proceeds toward the target, the MD simulation continues. Otherwise, it is discarded, and a new MD simulation is restarted, with new initial velocities randomly drawn from a Maxwell‑Boltzmann distribution. The discard‑and‑restart algorithm demonstrates efficacy and atomistic accuracy in capturing the folding pathways in several contexts: (1) fast‑folding small protein domains; (2) the folding intermediate of the prion protein PrP; and (3) the spontaneous partial unf..., , , # A Discard-and-Restart MD algorithm for the sampling of protein intermediate states This README file was generated by Alan Ianeselli on Feb 27th, 2025 ## DOI 10.5061/dryad.cc2fqz6h7 ## Date of Data Collection 2023 - 2024 ## Contributors Alan Ianeselli, Yale University, New Haven CT, USA Joe Howard, Yale University, New Haven CT, USA Mark B Gerstein, Yale University, New Haven CT, USA ## Summary This repository is integral to our research paper, and contains the data that support the findings of our study in order to ensure transparency and reproducibility. It includes the frames and trajectories generated using the discard-and-restart (D&R) algorithm as well as the Python script and model files. ## Description of the data and file structure The data for each protein is contained in the respective folder (beta_hairpin, Fip35, Prion, TrpCage_explicit, TrpCage_implicit, Tubulin, Villin_explicit, Villin_implicit). Pca_model.pkl is the file for the pca model used to calculate the...,