Learning multistate kinetics with a variational multistate committor network

Abstract

The long-time dynamics of complex molecular systems often involves rare transitions across networks of metastable states. Building on transition-path theory, which provides a rigorous framework for describing rare transitions between two metastable states, we introduce the variational multistate committor network (VMCN), a neural framework that learns the probabilities of reaching each metastable state directly from molecular simulation data. From this representation, VMCN identifies state-specific commitment, candidate transition regions and committor-consistent pathways between state pairs, and an effective kinetic network characterized by transition rates. The model is trained using finite time-lag trajectory data together with boundary conditions defined on conservative state cores. Applications to a triple-well potential, trialanine isomerization, and the $c$--ring rotation in the V$_{\rm o}$ domain of a vacuolar ATPase show that VMCN recovers metastable organization, provides committor-consistent descriptions of transition mechanisms, and estimates state-to-state kinetics. VMCN further provides diagnostics for incomplete state decompositions and enables adaptive exploration of candidate metastable states and their connecting regions. By integrating VMCN with generative committor-guided path sampling (Gen-COMPAS) for chignolin, we start from two end point structures, identify a misfolded state and a candidate folding intermediate, and we direct subsequent sampling toward the resulting multistate transition network.