Improving Convergence of Replica-Exchange Simulations through Coupling to a High-Temperature Structure Reservoir

Okur, Asim; Roe, Daniel R.; Cui, Guoxin; Hornak,; Simmerling, Carlos

doi:10.1021/ct600263e

Cited by 80 publications

(149 citation statements)

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“…The values are computed over the entire (post-equilibration) REMD ensemble. The simulations include standard REMD (black line, from our previously published data 28 ) along with two simulations in which the REMD replicas were coupled to the non-Boltzmann ensemble. In one simulation, the standard exchange criterion (eq.…”

Section: System and Resultsmentioning

confidence: 99%

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Coupling of Replica Exchange Simulations to a Non-Boltzmann Structure Reservoir

2007

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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 since 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 (>100ns) 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.Conformational sampling is crucial to simulating biologically relevant events in atomic detail, particularly when correct Boltzmann-weighted populations are required. Trapping in local energy minima often impairs complete exploration of conformational space. The challenges and improvements in conformational sampling have been discussed in several reviews 1,2 .One popular approach to overcoming poor sampling in biomolecular simulation is the replica exchange method (also known as parallel tempering) 3-5 . In replica exchange molecular dynamics (REMD) 6 , a series of molecular dynamics simulations (replicas) are performed for the system of interest. In the original form of REMD, each replica is an independent realization of the system, coupled to a thermostat at a different temperature.

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Section: System and Resultsmentioning

confidence: 99%

“…4). We implemented the resulting algorithm into the widely-used Amber program 31 , and we describe below the results obtained for a non-trivial model peptide that we have previously studied using standard and reservoir REMD 28 .…”

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Coupling of Replica Exchange Simulations to a Non-Boltzmann Structure Reservoir

2007

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“…The application of the REMD method to larger protein-glycan systems requires a large number of replicas. There have been several attempts to reduce the number of replicas, such as using REMD with a hybrid explicit/implicit solvation model (Okur et al 2006), solute tempering (Liu et al 2005), and REMD coupled to a high-temperature structure reservoir (Okur et al 2007). Such methods and further methodological developments could lead to accurate free-energy calculations of protein-glycan binding, and help explore the relationship between the flexibility of glycans and their specific recognition.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

Conformational flexibility of N-glycans in solution studied by REMD simulations

Nishima

Miyashita³

et al. 2012

Biophys Rev

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Protein-glycan recognition regulates a wide range of biological and pathogenic processes. Conformational diversity of glycans in solution is apparently incompatible with specific binding to their receptor proteins. One possibility is that among the different conformational states of a glycan, only one conformer is utilized for specific binding to a protein. However, the labile nature of glycans makes characterizing their conformational states a challenging issue. All-atom molecular dynamics (MD) simulations provide the atomic details of glycan structures in solution, but fairly extensive sampling is required for simulating the transitions between rotameric states. This difficulty limits application of conventional MD simulations to small fragments like di-and tri-saccharides. Replica-exchange molecular dynamics (REMD) simulation, with extensive sampling of structures in solution, provides a valuable way to identify a family of glycan conformers. This article reviews recent REMD simulations of glycans carried out by us or other research groups and provides new insights into the conformational equilibria of N-glycans and their alteration by chemical modification. We also emphasize the importance of statistical averaging over the multiple conformers of glycans for comparing simulation results with experimental observables. The results support the concept of "conformer selection" in protein-glycan recognition.

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“…This involves multiple ͑n͒ replicas at max , allowing the system to spend more time at this -value so that alternative conformations can be reached in shorter overall simulation time. This is reminiscent of the J-walking method 8 or finite reservoir simulations, 9,10 where a reservoir of structures is pregenerated at the highest temperature or Hamiltonian ͑T max / max ͒ and then "coupled" to REMD to get correct ensembles at lower values of T or . However, the concept of a degenerate T max / max is an integral part of REMD requiring no precalculation.…”

Section: Introductionmentioning

confidence: 99%

Hamiltonian replica exchange molecular dynamics using soft-core interactions

Hritz

Oostenbrink

2008

The Journal of Chemical Physics

132

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To overcome the problem of insufficient conformational sampling within biomolecular simulations, we have developed a novel Hamiltonian replica exchange molecular dynamics ͑H-REMD͒ scheme that uses soft-core interactions between those parts of the system that contribute most to high energy barriers. The advantage of this approach over other H-REMD schemes is the possibility to use a relatively small number of replicas with locally larger differences between the individual Hamiltonians. Because soft-core potentials are almost the same as regular ones at longer distances, most of the interactions between atoms of perturbed parts will only be slightly changed. Rather, the strong repulsion between atoms that are close in space, which in many cases results in high energy barriers, is weakened within higher replicas of our proposed scheme. In addition to the soft-core interactions, we proposed to include multiple replicas using the same Hamiltonian/level of softness. We have tested the new protocol on the GTP and 8-Br-GTP molecules, which are known to have high energy barriers between the anti and syn conformation of the base with respect to the sugar moiety. During two 25 ns MD simulations of both systems the transition from the more stable to the less stable ͑but still experimentally observed͒ conformation is not seen at all. Also temperature REMD over 50 replicas for 1 ns did not show any transition at room temperature. On the other hand, more than 20 of such transitions are observed in H-REMD using six replicas ͑at three different Hamiltonians͒ during 6.8 ns per replica for GTP and 12 replicas ͑at six different Hamiltonians͒ during 8.7 ns per replica for 8-Br-GTP. The large increase in sampling efficiency was obtained from an optimized H-REMD scheme involving soft-core potentials, with multiple simulations using the same level of softness. The optimization of the scheme was performed by fast mimicking ͓J. Hritz and C. Oostenbrink, J. Chem. Phys. 127, 204104 ͑2007͔͒.

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Improving Convergence of Replica-Exchange Simulations through Coupling to a High-Temperature Structure Reservoir

Cited by 80 publications

References 58 publications

Coupling of Replica Exchange Simulations to a Non-Boltzmann Structure Reservoir

Coupling of Replica Exchange Simulations to a Non-Boltzmann Structure Reservoir

Conformational flexibility of N-glycans in solution studied by REMD simulations

Hamiltonian replica exchange molecular dynamics using soft-core interactions

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