Re: Umbrella Sampling of Sugar Pseudorotation

From: Aaron Larsen (
Date: Mon Feb 03 2014 - 15:47:38 CST

Thank you very much for you reply. I believe that I have good starting
points for the force constants and equilibrium values of the restraints.
You're explanations should be sufficient to enable me to give this
experiment a go.


On Mon, Feb 3, 2014 at 4:12 PM, Aron Broom <> wrote:

> That sounds mostly right. Maybe a few points of confusion:
> 1) You don't necessarily need to pre-generate all the coordinates. You
> can start from a single structure and the restraint you apply should get
> you where you want to be. Keep in mind that because the energy landscape
> isn't flat, whatever angle you are looking at won't have a mean at the
> value of your restraint.
> 2) This is good. You may not need to minimize. It depends on how strong
> the restraints are, and how far from the restraint value you are starting.
> Minimizing is probably fairly safe, but check the final structures from
> the minimization to ensure nothing got mangled.
> 3) This is the confusing line. I'm not sure what you mean about a
> specific energy in a direction. Once you have the harmonic restraint you
> applied in 2, you have all you need. You do of course need to choose the
> equilibrium value and force constant for that restraint, but you'd do that
> in 2. So all you need to do here is run the simulation for some amount of
> time.
> 4) You don't need to compile the trajectories together. All you need to
> do is setup the colvars in NAMD to output the value of your restraint, and
> then use WHAM on those lists of values. Each window should have its own
> file and it's own force constant and equilibrium value.
> There are two main stumbling points with Umbrella Sampling, one at the
> beginning and one at the end:
> In the beginning, the problem you'll face is choosing the right force
> constants and equilibrium values for your restraints. In theory there are
> no wrong choices, as any choice can help define your PMF, but practically,
> you want the fewest number of windows that overlap with adjacent windows to
> span your reaction coordinate. Regions on the PMF where the slope is steep
> will be hard to explore, because the coordinate will tend to move down that
> slope. Not all windows need to use the same force constant, and the
> spacing between windows does not need to be even.
> At the end, the resulting PMF is only meaningful (accurate?) if the
> simulations in ALL the windows have reached equilibrium. That is, have all
> settled into whatever energy minimum is created by the combination of the
> native landscape and the restraint. It's generally very hard to know when
> this has happened. The easiest solution on a broad scale is to do your
> umbrella sampling twice, with different starting coordinates, and different
> langevin seeds for the thermostat. Then, once you've run for some amount
> of time that you hope will be good, compile both PMFs and see if they are
> equivalent. If they are not, you need to run for longer. Obviously, this
> also means you need to be trimming off the first part of each window's
> trajectory, since the assumption is that part isn't at an equilibrium value.
> On Mon, Feb 3, 2014 at 2:40 PM, Dan F. X. Martingano <>wrote:
>> Unsubscribe
>> > On Feb 3, 2014, at 2:36 PM, "Aaron Larsen" <
>>> wrote:
>> >
>> > Hello,
>> >
>> > I have recently performed equilibrium calculations on short
>> oligonucleotides to investigate factors influencing the pseudorotation of
>> the sugar pucker. I would like to extend this work to include Umbrella
>> sampling to establish the energy landscape along this coordinate.
>> >
>> > There have been some similar questions asked here but none seem to
>> apply very directly to my situation.
>> >
>> > First, I would like to establish that I have the correct notion as to
>> the steps involved in this process.
>> >
>> > 1) Generate a series of coordinates for a given system along the chosen
>> reaction coordinate. In my case, this would be a nucleotide with different
>> values, P, for the sugar pucker.
>> >
>> > 2) For each set of coordinates, apply a restraint and then minimize the
>> system.
>> >
>> > 3) For each system. apply a specific energy in a particular direction
>> and record the resulting trajectories.
>> >
>> > 4) Compile the trajectory files and use WHAM to investigate the PMF
>> along the chosen coordinate.
>> >
>> > Assuming that this is correct, is there any tutorial that can get me
>> started on this process? I was unable to find reference to Umbrella
>> sampling in the tutorial on the webpage but it might be covered by a
>> different term.
>> >
>> > Best,
>> > Aaron
>> >
>> >
> --
> Aron Broom M.Sc
> PhD Student
> Department of Chemistry
> University of Waterloo

Aaron Larsen, Ph.D.
Harvard University Department of Chemistry and Chemical Biology
Harvard Medical School Department of Genetics
Mobile: 617-319-3782
FAX: 617-643-3328

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