title: Coupling of replica exchange simulations to a non-Boltzmann structure reservoir.
abstract: Computing converged ensemble properties remains challenging for large biomolecules. Replica exchange molecular dynamics (REMD) can significantly increase the efficiency of conformational sampling by using high temperatures to escape kinetic traps. Several groups, including ours, introduced the idea of coupling replica exchange to a pre-converged, Boltzmann-populated reservoir, usually at a temperature higher than that of the highest temperature replica. This procedure reduces computational cost because the long simulation times needed for extensive sampling are only carried out for a single temperature. However, a weakness of the approach is that the Boltzmann-weighted reservoir can still be difficult to generate. We now present the idea of employing a non-Boltzmann reservoir, whose structures can be generated through more efficient conformational sampling methods. We demonstrate that the approach is rigorous and derive a correct statistical mechanical exchange criterion between the reservoir and the replicas that drives Boltzmann-weighted probabilities for the replicas. We test this approach on the trpzip2 peptide and demonstrate that the resulting thermal stability profile is essentially indistinguishable from that obtained using very long (>100 ns) standard REMD simulations. The convergence of this reservoir-aided REMD is significantly faster than for regular REMD. Furthermore, we demonstrate that modification of the exchange criterion is essential; REMD simulations using a standard exchange function with the non-Boltzmann reservoir produced incorrect results.
authors.affiliation: Quantum Theory Project, Department of Chemistry, University of Florida, Gainesville, Florida 32611, USA. roitberg@qtq.ufl.edu
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Roitberg
authors.forename: Asim
authors.initials: A
authors.lastname: Okur
authors.forename: Carlos
authors.initials: C
authors.lastname: Simmerling
mesh_terms: D003198:Computer Simulation; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry*; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary
chemical_list: D010455:Peptides