Efficiency of Adaptive Temperature-Based Replica Exchange for Sampling Large-Scale Protein Conformational Transitions

Abstract

Temperature-based replica exchange (RE) is now considered a principal technique for enhanced sampling of protein conformations. It is also recognized that existence of sharp cooperative transitions (such as protein folding/unfolding) can lead to temperature exchange bottlenecks and significantly reduce the sampling efficiency. Here, we revisit two adaptive temperature-based RE protocols, namely, exchange equalization (EE) and current maximization (CM), that were previously examined using atomistic simulations (Lee and Olson, J. Chem. Physics 2011, 134, 24111). Both protocols aim to overcome exchange bottlenecks by adaptively adjusting the simulation temperatures, either to achieve uniform exchange rates (in EE) or to maximize temperature diffusion (CM). By designing a realistic yet computationally tractable coarse-grained protein model, one can sample many reversible folding/unfolding transitions using conventional constant temperature molecular dynamics (MD), standard REMD, EE-REMD, and CM-REMD. This allows rigorous evaluation of the sampling efficiency, by directly comparing the rates of folding/unfolding transitions and convergence of various thermodynamic properties of interest. The results demonstrate that both EE and CM can indeed enhance temperature diffusion compared to standard RE, by ∼3and over 10-fold, respectively. Surprisingly, the rates of reversible folding/unfolding transitions are similar in all three RE protocols. The convergence rates of several key thermodynamic properties, including the folding stability and various 1D and 2D free energy surfaces, are also similar. Therefore, the efficiency of RE protocols does not appear to be limited by temperature diffusion, but by the inherent rates of spontaneous large-scale conformational rearrangements. This is particularly true considering that virtually all RE simulations of proteins in practice involve exchange attempt frequencies (∼ps −1 ) that are several orders of magnitude faster than the slowest protein motions (∼μs −1 ). Our results also suggest that the efficiency of RE will not likely be improved by other protocols that aim to accelerate exchange or temperature diffusion. Instead, protocols with some types of guided tempering will likely be necessary to drive faster large-scale conformational transitions.

Efficacy of independence sampling in replica exchange simulations of ordered and disordered proteins

“…17,20 Indeed, further examination of key thermodynamic properties suggests potential benefits of enhanced mixing of T-REis, despite its inability to directly accelerate reversible folding/unfolding transitions. We compare the distributions of the number of native hydrogen bonds of GB1p at 270 K derived from T-RE and T-REis in Figure 4.…”

“…In particular, the free energy barriers of cooperative transitions are dominated by entropic components, such that tempering is fundamentally ineffective for driving faster transitions. 17 Nonetheless, there appear to be some benefits of enhanced mixing in achieving slightly better convergence of various thermodynamic properties, despite the lack of direct effects on conformational sampling. In addition, we anticipate that the simple independence sampling scheme could be much more effective when incorporated with various Hamiltonian replica exchange protocols, particularly when the underlying energy landscapes are modified via biasing potentials or selected force field components to reduce the transition energy barriers.…”

“…17–24 The underlying energy barriers of the simulated system have a significant influence on the sampling efficiency. T-RE can be more efficient than conventional MD simulation as long as the activation enthalpies of conformational transitions are positive.…”

Computational membrane biophysics: From ion channel interactions with drugs to cellular function

“…However, it should be noted that there is no clear justification for a “good” exchange rate because there may be still some aggregations of replicas in the temperature space[68]. In this case, an adaptive T-REMD can be implemented to avoid such aggregations[69]. Note that T-REMD or REST2 are particularly useful for simulation systems with unknown reaction coordinates for describing binding/unbinding events or correlation between binding/unbinding and conformational changes of ion channels.…”

Accelerate Sampling in Atomistic Energy Landscapes Using Topology-Based Coarse-Grained Models

“…Nonetheless, the efficiency of T-RE can be severely limited by the presence of sharp cooperative conformational transitions such as protein folding 10,11 . Importantly, this limitation cannot be overcome by various T-RE variants designed to accelerate either exchanges or diffusion in temperature space 12 .…”