A critical perspective on Markov state model treatments of protein–protein association using coarse-grained simulations

Atomic-level information is essential to explain the specific interactions governing protein–protein recognition in terms of structure and dynamics. Of particular interest is a characterization of the time-dependent kinetic aspects of protein–protein association and dissociation. A powerful framework to characterize the dynamics of complex molecular systems is provided by Markov State Models (MSMs). The central idea is to construct a reduced stochastic model of the full system by defining a set of conformational featured microstates and determining the matrix of transition probabilities between them. While a MSM framework can sometimes be very effective, different combinations of input featurization and simulation methods can significantly affect the robustness and the quality of the information generated from MSMs in the context of protein association. Here, a systematic examination of a variety of MSMs methodologies is undertaken to clarify these issues. To circumvent the uncertainties caused by sampling issues, we use a simplified coarse-grained model of the barnase–barstar protein complex. A sensitivity analysis is proposed to identify the microstates of an MSM that contribute most to the error in conjunction with the transition-based reweighting analysis method for a more efficient and accurate MSM construction.