[gmx-developers] Re:Re:Re: Energy Minimization

[Leontyev Igor]

> Igor Leontyev wrote:
>> There is no rigorous prove in the manual section 3.10 that the finer
>> energy minimization is not essential for MD of complex biological system.

> Tsjerk Wassenaar wrote:
> There doesn't need to be. The point of doing MD is to see a system cross
> energy barriers (or, rarely, to see that it doesn't). Thus it is
> expected to move from the starting position, and at a certain point of
> EM, the structure is good enough, i.e. close to one in the ensemble of
> interest so that equilibration happens reasonably quickly and without
> failures of the integrator.



The goal of doing any simulation is modeling actuality. In real proteins a
rate of crossing some potential barriers can be in a scale of microseconds
or even larger, which is not feasible for MD. Therefore, we should start
simulation from the configuration which is close to "the ensemble of
interest" to explore an essential part of the phase space. However, it's
even not always known what part of the phase space is essential. Therefore,
we may just want to find the lowest energy local minimum. A finer EM
algorithm suppose to results to lower energy. If it's not the case we always
can use optimized structure from the previous gruff minimization step. But
if the finer EM algorithm would bring our system to another (lower energy)
local minimum separated from the first one by a high barrier (>>kT) then we
will observe in MD a different dynamics (explore a part of the phase space
different from the one corresponding to the gruffly minimized
configuration). Or, is there any indication that the finer EM algorithm can
not bring us to other local minimum?

> Tsjerk Wassenaar wrote:
>There doesn't need to be. That section describes the methods. By the
>way, I haven't seen rigorous prove against the existence of
>leprechauns or the monster of Loch Ness yet.

Sure. Thus, the section 3.10 can not be used as an argument or theorem to
prove something.

> Tsjerk Wassenaar wrote:
> Sorry, I'm not sure what the "second example" or "simple option" to
> which you refer are.

"Second example" is an optimization of hydrogen positions with frozen heavy
atoms which typically is employed for continuum electrostatic pKa
calculations. The "Simple option" is a capability to carry out the "cg"
minimization with constraints.

> Tsjerk Wassenaar wrote:
> You did steepest-descent EM on a system with lots of frozen atoms, if I
> understand correctly. You then switched to L-BFGS with frozen atoms,
> which starts with an estimated Hessian. The Hessian updates then are
> based on calculated forces whose components are unbalanced because of
> the constraints. Such a procedure could well be numerically unstable.
> You may be proving that. Try a second L-BFGS from your first L-BFGS
> endpoint and see where it goes. If it's some different place, then you
> may be demonstrating that this minimizer can't deal with the
> (artificial) problem you have constructed.
>

Similar problem has been observed for polarizable benzene molecule without
constraints. After finer optimization of a single benzene molecule, 2 shell
particles were relocated from the position of their heavy atoms (ground
state) to position of neighboring heavy atoms (very high energy local
minimum due to a large bond stretching energy penalty). The artifact I have
reported earlier in the thread "Polarizable simulations in Gromacs"

> "Frozen" might have meant with respect to the initial configuration, or
> as someone pointed out, that the atomic positions were merely never
> updated. So (for example) if the initial frame was translated for some
> reason, it could still be translated in the output. This could produce a
> deceptive frameshift. You can test for this by doing what I said -
> centering the input and output structures on the same frozen atom
> post-mdrun.

Anyhow, the terminology does not affect the problem: the
optimization of water-hydrogens with frozen positions of water-oxygens
results to the structure with shifted water-oxygens.