Integrative generalized master equation: A method to study long-timescale biomolecular dynamics via the integrals of memory kernels

The generalized master equation (GME) provides a powerful approach to study biomolecular dynamics via non-Markovian dynamic models built from molecular dynamics (MD) simulations. Previously, we have implemented the GME, namely the quasi Markov State Model (qMSM), where we explicitly calculate the memory kernel and propagate dynamics using a discretized GME. qMSM can be constructed with much shorter MD trajectories than the MSM. However, since qMSM needs to explicitly compute the time-dependent memory kernels, it is heavily affected by the numerical fluctuations of simulation data when applied to study biomolecular conformational changes. This can lead to numerical instability of predicted long-time dynamics, greatly limiting the applicability of qMSM in complicated biomolecules. We present a new method, the Integrative GME (IGME), in which we analytically solve the GME under the condition when the memory kernels have decayed to zero. Our IGME overcomes the challenges of the qMSM by using the time integrations of memory kernels, thereby avoiding the numerical instability caused by explicit computation of time-dependent memory kernels. Using our solutions of the GME, we have developed a new approach to compute long-time dynamics based on MD simulations in a numerically stable, accurate and efficient way. To demonstrate its effectiveness, we have applied the IGME in three biomolecules: the alanine dipeptide, FIP35 WW-domain, and Taq RNA polymerase. In each system, the IGME achieves significantly smaller fluctuations for both memory kernels and long-time dynamics compared to the qMSM. We anticipate that the IGME can be widely applied to investigate biomolecular conformational changes.