### Abstract

Milestoning is a procedure to compute the time evolution of complicated processes such as barrier crossing events or long diffusive transitions between predefined states. Milestoning reduces the dynamics to transition events between intermediates (the milestones) and computes the local kinetic information to describe these transitions via short molecular dynamics (MD) runs between the milestones. The procedure relies on the ability to reinitialize MD trajectories on the milestones to get the right kinetic information about the transitions. It also rests on the assumptions that the transition events between successive milestones and the time lags between these transitions are statistically independent. In this paper, we analyze the validity of these assumptions. We show that sets of optimal milestones exist, i.e., sets such that successive transitions are indeed statistically independent. The proof of this claim relies on the results of transition path theory and uses the isocommittor surfaces of the reaction as milestones. For systems in the overdamped limit, we also obtain the probability distribution to reinitialize the MD trajectories on the milestones, and we discuss why this distribution is not available in closed form for systems with inertia. We explain why the time lags between transitions are not statistically independent even for optimal milestones, but we show that working with such milestones allows one to compute mean first passage times between milestones exactly. Finally, we discuss some practical implications of our results and we compare milestoning with Markov state models in view of our findings.

Original language | English (US) |
---|---|

Article number | 174102 |

Journal | Journal of Chemical Physics |

Volume | 129 |

Issue number | 17 |

DOIs | |

State | Published - 2008 |

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### ASJC Scopus subject areas

- Physics and Astronomy(all)
- Physical and Theoretical Chemistry
- Medicine(all)

### Cite this

*Journal of Chemical Physics*,

*129*(17), [174102]. https://doi.org/10.1063/1.2996509

**On the assumptions underlying milestoning.** / Vanden Eijnden, Eric; Venturoli, Maddalena; Ciccotti, Giovanni; Elber, Ron.

Research output: Contribution to journal › Article

*Journal of Chemical Physics*, vol. 129, no. 17, 174102. https://doi.org/10.1063/1.2996509

}

TY - JOUR

T1 - On the assumptions underlying milestoning

AU - Vanden Eijnden, Eric

AU - Venturoli, Maddalena

AU - Ciccotti, Giovanni

AU - Elber, Ron

PY - 2008

Y1 - 2008

N2 - Milestoning is a procedure to compute the time evolution of complicated processes such as barrier crossing events or long diffusive transitions between predefined states. Milestoning reduces the dynamics to transition events between intermediates (the milestones) and computes the local kinetic information to describe these transitions via short molecular dynamics (MD) runs between the milestones. The procedure relies on the ability to reinitialize MD trajectories on the milestones to get the right kinetic information about the transitions. It also rests on the assumptions that the transition events between successive milestones and the time lags between these transitions are statistically independent. In this paper, we analyze the validity of these assumptions. We show that sets of optimal milestones exist, i.e., sets such that successive transitions are indeed statistically independent. The proof of this claim relies on the results of transition path theory and uses the isocommittor surfaces of the reaction as milestones. For systems in the overdamped limit, we also obtain the probability distribution to reinitialize the MD trajectories on the milestones, and we discuss why this distribution is not available in closed form for systems with inertia. We explain why the time lags between transitions are not statistically independent even for optimal milestones, but we show that working with such milestones allows one to compute mean first passage times between milestones exactly. Finally, we discuss some practical implications of our results and we compare milestoning with Markov state models in view of our findings.

AB - Milestoning is a procedure to compute the time evolution of complicated processes such as barrier crossing events or long diffusive transitions between predefined states. Milestoning reduces the dynamics to transition events between intermediates (the milestones) and computes the local kinetic information to describe these transitions via short molecular dynamics (MD) runs between the milestones. The procedure relies on the ability to reinitialize MD trajectories on the milestones to get the right kinetic information about the transitions. It also rests on the assumptions that the transition events between successive milestones and the time lags between these transitions are statistically independent. In this paper, we analyze the validity of these assumptions. We show that sets of optimal milestones exist, i.e., sets such that successive transitions are indeed statistically independent. The proof of this claim relies on the results of transition path theory and uses the isocommittor surfaces of the reaction as milestones. For systems in the overdamped limit, we also obtain the probability distribution to reinitialize the MD trajectories on the milestones, and we discuss why this distribution is not available in closed form for systems with inertia. We explain why the time lags between transitions are not statistically independent even for optimal milestones, but we show that working with such milestones allows one to compute mean first passage times between milestones exactly. Finally, we discuss some practical implications of our results and we compare milestoning with Markov state models in view of our findings.

UR - http://www.scopus.com/inward/record.url?scp=55949099868&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=55949099868&partnerID=8YFLogxK

U2 - 10.1063/1.2996509

DO - 10.1063/1.2996509

M3 - Article

C2 - 19045328

AN - SCOPUS:55949099868

VL - 129

JO - Journal of Chemical Physics

JF - Journal of Chemical Physics

SN - 0021-9606

IS - 17

M1 - 174102

ER -