Deriving Implicitly Polarized Charges in mdgx: Introduction
This tutorial will guide users through the process of creating Implicitly
Polarized Charges (IPolQ) for their molecules. Implicitly polarized charges
are intended to approximate the correct mean field electron density of a
molecule in a condensed phase medium, which is to say the best fixed partial
charge distribution if explicit polarization (Drude oscillators, fluctuating
charges, inducible multipoles) is not in the simulation. The solvent
environment for us has always been water, although other solvents or
environments are also fair game. The IPolQ method, first published in 2013, is
intended as a successor to charge sets developed from vacuum phase
Hartree-Fock / 6-31G* calculations. This tutorial is written with lots of
detail, but the purpose is not to dissuade beginners. Each operation in the
tutorial should be simple by itself; the details are provided to help readers
see the broader context, understand the control they have over their
simulations, answer frequently asked questions, and hopefully prevent new users
from taking wrong turns.
Stage 1: The molecule in many guises
Stage 2: QM with and without the time-averaged solvent
density
Stage 3: Fitting charges
Stage 4: Iterate to convergence
Because the HF / 6-31G* method is known to over-polarize charges in some
contexts, it relies on a fortuitous cancellation of errors to deliver results.
IPolQ starts from a set of assumptions about the nature of the molecule and a
detailed representation of the electrostatic field due to the condensed phase
medium. This new method is not without approximations, and as we show in the
supporting
information to the 2013 publication one of these approximations (governing
the way in which the energy penalty for polarizing the molecule prevents
excessive charge redistribution) breaks down fairly quickly. However, the
thrust of the idea remains correct: molecules in a polar condensed solvent
should respond to the electrostatic field of that solvent by increasing the
charge separation of their polar groups. The IPolQ method incorporates a
time-averaged portrait of the charge density in the surrounding matter, which
is a step up from vacuum phase quantum calculations, and this treatment permits
higher levels of quantum theory to directly account for effects such as
electron correlation.
The extended IPolQ scheme, published in 2014, adds the advantage of
deriving charges for a molecule in vacuum as well, then expressing the IPolQ
charges as a perturbation of the vacuum phase charges. This adds utility when
fitting other parameters for the molecule's bonds, bond angles, and dihedrals:
these parameters are typically fitted to gas-phase quantum data, and the charge
set used in fitting the parameters should match. The IPolQ framework for
developing a complete force field is then to fit bonded parameters in the
context of vacuum phase charges and pair these with the IPolQ charges in
actual simulations. This fulfills the approximation that the bonded parameters
are largely unaffected by changes in the charge state, and that the
consequences of dunking the molecule in a polar medium (water) are primarily
electrostatic. Philosophically, this is a superior position in force field
development. In practice, we have observed the results to be promising. Our
published and forthcoming results show that it is important to have a polarized
charge set, but the nuance of deriving bonded parameters in the context of a
corresponding vacuum phase charge set is a minor advantage. Parameters derived
using the traditional HF / 6-31G* workflow probably suffer slightly from the
mismatch of phases at different stages in the calculation, but they appear on
the whole seaworthy.
This tutorial will take the case of glycerol, a small, water-soluble
molecule with several polar groups of its own and many rotatable bonds. This
tutorial will make use of the mdgx program within AmberTools, and
the ORCA quantum chemistry package available free to academics
here. mdgx also
supports the
Gaussian package for its IPolQ
calculations, and links to other packages may be added in the future.
mdgx has an on-board manual that lists all keywords relevant to
its various modules: in the case of this tutorial users can run
${AMBERHOME}/bin/mdgx (-IPOLQ, -CONFIGS, -FITQ) at
any time to see the relevant documentation. Because of glycerol's size, the
quantum calculations will run quickly, but if this were an actual fitting
additional MD would be needed to obtain convergent charge densities. More
conformations might be warranted to ensure that the charges do not depend
strictly on certain rotations of each hydroxyl group, but given the symmetry
of the molecule and the fact that conformations which have one hydroxyl group
make a hydrogen bond to another on the same molecule are likely to be invalid,
the handful of conformations that will be created in this tutorial are probably
sufficient. For feature requests, questions about this tutorial, or further
advice on force field development, users may contact Dave Cerutti directly at
dscerutti<at>gmail<dot>com.
Publications relevant to the IPolQ scheme include:
- D.S. Cerutti, J.E. Rice, W.C. Swope, and D.A. Case. (2013) "Derivation of
Fixed Partial Charges for Amino Acids Accommodating a Specific Water Model and
Implicit Polarization." J. Phys. Chem. B 117: 2328-2338.
link
- D.S. Cerutti, W.C. Swope, J.E. Rice, and D.A. Case. (2014) "ff14ipq: A
Self-Consistent Force Field for Condensed-Phase Simulations of Proteins."
J. Chem. Theory Comput. 10: 4515-4534.
link
- K.T. Debiec, D.S. Cerutti, L.R. Baker, A.M. Gronenborn, D.A. Case, and L.T.
Chong. (2016) "Further along the Road Less Traveled: AMBER ff15ipq, an
Original Protein Force Field Built on a Self-Consistent Physical Model."
J. Chem. Theory Comput. 12: 3926-3947.
link
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