Applied causality to infer protein dynamics and kinetics

arXiv:2508.12060v2 Announce Type: replace
Abstract: The use of generative machine learning models, trained on the experimentally resolved structures deposited in the protein data bank, is an attractive approach to sampling conformational ensembles of proteins. However, the ensembles generated by these models lack timescale or causal information. We use the structural ensembles generated from AlphaFold2 at a range of MSA depths to parameterize the potential of mean force of an overdamped, memory-free, coarse-grained Langevin equation. This approach couples the AlphaFold2 ensembles to a causal model, allowing us to estimate the timescales spanned by the ensembles generated at each MSA depth. Performing this analysis on six variants of HIV-1 protease, we confirm an inverse relationship between MSA depth and the timescale of an ensemble’s conformational fluctuations. The MSA depth essentially serves as a conformational restraint, and AlphaFold2 is generally able to probe timescales at or below those seen in microsecond-long, unbiased molecular dynamics simulations. We conclude by generalizing this approach to other generative structural ensemble-prediction methods as well as co-folding models, in this case the biologically functional HIV-1 protease dimer.