Modeling cryo-EM structures in alternative states with AlphaFold2-based models and density-guided simulations.

ABSTRACT: Modeling atomic coordinates into a target cryo-electron microscopy map is a crucial step in structure determination. Despite recent advances, proteins with multiple functional states remain a challenge - particularly when suitable molecular templates are unavailable for certain states, and the map resolution is not high enough to build de novo models. This is a common scenario, for example, among pharmacologically relevant membrane-bound receptors and transporters. Here, we introduce a refinement approach in which (i) several initial models are generated by stochastic subsampling of the multiple sequence alignment (MSA) space in AlphaFold2, (ii) the resulting models are subjected to structure-based k-means clustering, iii) density-guided molecular dynamics simulations are performed from th

SUBMITTER: Shugaeva T 

PROVIDER: S-EPMC12575730 | biostudies-literature | 2025 Oct

REPOSITORIES: biostudies-literature