Hamiltonian Switch Metropolis Monte Carlo Simulations for Improved Conformational Sampling of Intrinsically Disordered Regions Tethered to Ordered Domains of Proteins

[Image: see text] There is growing interest in the topic of intrinsically disordered proteins (IDPs). Atomistic Metropolis Monte Carlo (MMC) simulations based on novel implicit solvation models have yielded useful insights regarding sequence-ensemble relationships for IDPs modeled as autonomous units. However, a majority of naturally occurring IDPs are tethered to ordered domains. Tethering introduces additional energy scales and this creates the challenge of broken ergodicity for standard MMC sampling or molecular dynamics that cannot be readily alleviated by using generalized tempering methods. We have designed, deployed, and tested our adaptation of the Nested Markov Chain Monte Carlo sampling algorithm. We refer to our adaptation as Hamiltonian Switch Metropolis Monte Carlo (HS-MMC) sampling. In this method, transitions out of energetic traps are enabled by the introduction of an auxiliary Markov chain that draws conformations for the disordered region from a Boltzmann distribution that is governed by an alternative potential function that only includes short-range steric repulsions and conformational restraints on the ordered domain. We show using multiple, independent runs that the HS-MMC method yields conformational distributions that have similar and reproducible statistical properties, which is in direct contrast to standard MMC for equivalent amounts of sampling. The method is efficient and can be deployed for simulations of a range of biologically relevant disordered regions that are tethered to ordered domains.