Bridging Dimensionality Reduction and Stochastic Sampling: The DA2-MC Algorithm for Protein Dynamics

Elucidating protein dynamics and conformational changes is crucial for understanding their biological functions. This work introduces a data-driven accelerated conformational searching algorithm incorporating a Monte Carlo strategy, termed the DA2-MC method, which integrates dimensionality reduction techniques with Monte Carlo strategies to efficiently explore unknown protein conformations. The DA2-MC method was applied to investigate the folding mechanisms of two miniproteins, chignolin and WW domain, revealing their dynamic behavior in different conformational states at a reasonable computational cost. A Markov state model-based analysis of chignolin's folding pathway corroborated the dynamic insights obtained from the DA2-MC method. Moreover, free energy calculations initiated with the intermediate structures identified by DA2-MC yielded results consistent with published literature, affirming the method's reliability in accelerating conformational searches and reconstructing equilibrium properties. Collectively, the DA2-MC method emerges as an effective tool for efficiently exploring protein conformations, facilitating the identification of potential functional conformations on complex energy landscapes.