Characterization of the Three-Dimensional Free Energy Manifold for the Uracil Ribonucleoside from Asynchronous Replica Exchange Simulations

Abstract

Replica exchange molecular dynamics has emerged as a powerful tool for efficiently sampling free energy landscapes for conformational and chemical transitions. However, daunting challenges remain in efficiently getting such simulations to scale to the very large number of replicas required to address problems in state spaces beyond two dimensions. The development of enabling technology to carry out such simulations is in its infancy, and thus it remains an open question as to which applications demand extension into higher dimensions. In the present work, we explore this problem space by applying asynchronous Hamiltonian replica exchange molecular dynamics with a combined quantum mechanical/molecular mechanical potential to explore the conformational space for a simpleribonucleoside , using a newly developed software framework capable of executing >3,000 replicas with only enough resources to run 2,000 simultaneously, which may not be possible with traditional synchronous replica exchange approaches. Our results demonstrate 1.) the necessity of high dimensional sampling simulations for biological systems, even as simple as as a single ribonucleoside, 2.) the utility of asynchronous exchange protocols in managing simultaneous resource requirements expected in high dimensional sampling simulations. It is expected that more complicated systems will only increase in computational demand and complexity and thus the reported asynchronous approach may be increasingly beneficial in order to make such applications available to a broad range of computational scientists.

Exploring RNA structure and dynamics through enhanced sampling simulations

“…Conformational Landscapes. This is the wider group considered and includes papers discussing the conformational landscape of systems ranging from individual nucleosides [32,35,36], small loops [27,28,38,50], duplexes [30,46,49], stem-loops [31,36,37,39,40,43,47,48], and pseudoknots [33], up to larger aptamers [42,44], riboswitches [29,34], RNA:peptide [40], and RNA:protein complexes [41,45]. None of the applications to large RNA systems is designed to sample extensively the conformational space, which would be extremely expensive and probably counterproductive considering the force-field limitations discussed above.…”

“…DFT functionals are mostly used for QM calculations because they offer sufficient accuracy for estimating reaction barriers. Some works benefited from the usage of efficient SE methods that allow extensive sampling at the expense of some tuning and external corrections [32,59,66].…”

“…A more robust alternative is provided by replicaexchange US simulations, used for instance in Refs. [32,41,59], at least if continuous trajectories are analyzed and transition events are detected as discussed above for T-REMD ( Figure 2). We notice that several works related to catalysis took advantage of the string method in order to sample http://creativecommons.org/licenses/by-nc-nd/4.0/ a reactive pathway [60,62,64,67].…”

“…Chemical reactions are typically accomplished by biasing a combination of distances, where some describe newly formed or expired contacts and others enforce related proton transfers [59,60,64,65,66,67,69]. Dihedral angles can be used to enforce the exploration of multiple rotamers [21,24,26,27,32,43]. In some cases, the barriers associated to sugar repuckering were accelerated using pseudodihedrals [21,24,25,27,32].…”

Asynchronous replica exchange software for grid and heterogeneous computing

“…Replica Exchange (RE) algorithms[27, 28] are recognized as among the most powerful enhanced conformational sampling tools available,[29, 30, 31, 32, 33, 34] yielding converged results orders of magnitude faster than conventional approaches. [7] RE methods are based on replicating the system across combinations of thermodynamic and potential energy parameters[35] (in this work primarily alchemical receptor-ligand coupling λ and temperature T ), each evolving independently with the exception of occasional exchanges of thermodynamic parameters between replicas.…”