The problem with standard simulations
Chong, Saglam, and Zuckerman, Curr. Opin. Struct. Biol., 2017.
Generates unbiased, continuous pathways and rates with orders of magnitude less computing than standard MD.
Efficiency scales exponentially with the barrier.
von Neumann & Ulam “splitting strategy” (1950s)
Huber & Kim, Biophys. Journal (1996)
Zuckerman & Chong, Ann. Rev. Biophys. (2017)
Weighted ensemble MD focuses on transitions
Resampling procedure
How does resampling work?
time = 0 ps
probability =
Run MD
τ = 100 ps
progress coordinate
time = τ
τ = 100 ps
probability =
flux = 0
progress coordinate
Run MD
τ = 100 ps
probability =
flux = 0
progress coordinate
time = τ
probability =
time = 2τ
τ = 100 ps
flux = 0
progress coordinate
τ = 200 p
Run MD
time = 2τ
τ = 100 ps
probability =
flux = 0
progress coordinate
τ = 300 ps
time = 3τ
τ = 100 ps
probability =
flux = 0
progress coordinate
τ = 300 ps
Run MD
time = 3τ
τ = 100 ps
probability =
flux = 0
progress coordinate
t = 3τ
Probability =
τ = 400 ps
time = 4τ
flux = 0.00125 ps-1
τ = 100 ps
probability =
progress coordinate
τ = 400 ps
time = 4τ
τ = 100 ps
probability =
flux = 0.00125 ps-1
progress coordinate
τ = 400 ps
Run MD
time = 4τ
Flux = 0.5
τ = 100 ps
probability =
flux = 0.00125 ps-1
progress coordinate
No free lunch!
May miss slow motions orthogonal to the progress coordinate.
Worse case is “brute force” sampling of orthogonal motions.
However, we can switch progress coordinates “on-the-fly.”
Weighted ensemble MD greatly extends accessible timescales
10-15
(fs)
10-12
(ps)
10-9
(ns)
10-6
(μs)
10-3
(ms)
100
(s)
Surface
side chain
rotation
Bond vibration
Hinge bending
Protein folding
Loop motions
Standard MD (Anton)
Weighted ensemble MD
Protein binding
Large-scale conformational transitions