Deep Generative Markov State Models with Experimental Restraints

Abstract

A central challenge in molecular modeling is reconciling simulations with experimental observables, as force-field inaccuracies can distort equilibrium populations and long-timescale kinetics. While time-dependent restraints can improve simulated kinetics, time-dependent structural observables remain limited. Thus, most experimental data are time-averaged, informing equilibrium ensembles but not directly dynamics. Although ensemble refinement can improve thermodynamic accuracy, incorporating time-averaged observables into kinetic models remains difficult. Here, we introduce BICePs-reweighted Reversible DeepMSMs, combining Bayesian Inference of Conformational Populations (BICePs), variational learning of Markov processes, and maximum entropy (MaxEnt)/maximum caliber (MaxCal) principles to infer consistent thermodynamics and minimally perturbed kinetics. At its core is a reversible DeepMSM prior, obtained by applying an orthogonal transformation post-hoc to a pre-trained dynamics model (e.g., VAMPnet). This preserves the eigenspectrum exactly while yielding a valid transition matrix that is nonnegative, row-stochastic, and reversible. The reweighted model refines stationary populations, transition dynamics, and state-conditioned configurational landing densities. We validate the approach on a quadruple-well toy system and alanine dipeptide using backbone dihedral angles and J-coupling constants. In both systems, perturbing the observables induces predictable changes in the equilibrium ensemble and corresponding inferred kinetics. The resulting relaxation timescales and dynamical modes closely agree with analytical and MaxCal reference models. Furthermore, a diffusion-based generative model trained on MaxEnt landing densities produces physically realistic alanine dipeptide trajectories that reproduce thermodynamics and kinetics while satisfying the imposed experimental restraints.