This is a simple example of how Bayesian atom type sampling using reversible-jump Markov chain Monte Carlo (RJMCMC) [1] over SMARTS types might work.

This also provides a prototype and validation of the SMIRFF SMIRKS-based force field format, along with classes to parameterize OpenMM systems given SMIRFF .ffxml format files as provided here.

• examples/ - some toy examples - look here to get started
• smarty/ - simple toolkit illustrating the use of RJMCMC to sample over SMARTS-specified atom types; also contains forcefield.py for handling SMIRFF forcefield format.
• devtools/ - continuous integration and packaging scripts and utilities
• oe_license.txt.enc - encrypted OpenEye license for continuous integration testing
• .travis.yml - travis-ci continuous integration file
• utilities/ - some utility functionality relating to the project; initially, for conversion of parm@frosst modified frcmod files to SMIRFF XML.

Install miniconda first. On osx with bash, this is:

wget https://repo.continuum.io/miniconda/Miniconda2-latest-MacOSX-x86_64.sh
bash Miniconda2-latest-MacOSX-x86_64.sh -b -p $HOME/miniconda
export PATH="$HOME/miniconda/bin:${PATH}""

You must first install the OpenEye toolkit:

pip install -i https://pypi.anaconda.org/OpenEye/simple OpenEye-toolkits

Install other conda dependencies:

conda install --yes numpy networkx
conda install --yes -c omnia openmoltools

NOTE: We'll add a better way to install these dependencies via conda soon.

Install smarty from the smarty/ directory with:

pip install .

If you modify the smarty source code (rather than the examples), reinstall with

pip install . --upgrade

Check out the example in examples/parm@frosst/:

Atom types are specified by SMARTS matches with corresponding parameter names.

First, we start with a number of initial "base types" which are essentially indestructible (often generic) atom types, specified in atomtypes/basetypes.smarts:

% atom types
[#1]    hydrogen
[#6]    carbon
[#7]    nitrogen
[#8]    oxygen
[#9]    fluorine
[#15]   phosphorous
[#16]   sulfur
[#17]   chlorine
[#35]   bromine
[#53]   iodine

Note that lines beginning with % are comment lines.

We also specify a number of starting types, "initial types" which can be the same or different from the base types. These follow the same format, and atomtypes/basetypes.smarts can be reused unless alternate behavior is desired (such as starting from more sophisticated initial types).

Atom type creation moves has two options, one is using simple decorators (--decoratorbehavior=simple-decorators) and the other is combinatorial decorators (default).

The first option (simple-decorators) attempt to split off a new atom type from a parent atom type by combining (via an "and" operator, &) the parent atom type with a "decorator". The decorators are listed in AlkEtOH/atomtypes/decorators.smarts or parm@frosst/atomtypes/decorators.smarts:

% bond order
$([*]=[*])     double-bonded
$([*]#[*])     triple-bonded
$([*]:[*])     aromatic-bonded
% bonded to atoms
$(*~[#1])      hydrogen-adjacent
$(*~[#6])      carbon-adjacent
$(*~[#7])      nitrogen-adjacent
$(*~[#8])      oxygen-adjacent
$(*~[#9])      fluorine-adjacent
$(*~[#15])     phosphorous-adjacent
$(*~[#16])     sulfur-adjacent
$(*~[#17])     chlorine-adjacent
$(*~[#35])     bromine-adjacent
$(*~[#53])     iodine-adjacent
% degree
D1             degree-1
D2             degree-2
D3             degree-3
D4             degree-4
D5             degree-5
D6             degree-6
% valence
v1             valence-1
v2             valence-2
v3             valence-3
v4             valence-4
v5             valence-5
v6             valence-6
% total-h-count
H1             total-h-count-1
H2             total-h-count-2
H3             total-h-count-3
% aromatic/aliphatic
a              atomatic
A              aliphatic

Each decorator has a corresponding string token (no spaces allowed!) that is used to create human-readable versions of the corresponding atom types.

For example, we may find the atom type [#6]&H3 which is carbon total-h-count-3 for a C atom bonded to three hydrogens.

The second option (combinatorial-decorator) attempt to create the new atomtype adding an Alpha or Beta substituent to a basetype or an atomtype. This decorators are different from the simple-decorator option and do not have atom types or bond information on it. The new decorators are listed in AlkEtOH/atomtypes/new-decorators.smarts and parm@frosst/atomtypes/new-decorators.smarts:

% total connectivity
X1             connections-1
X2             connections-2
X3             connections-3
X4             connections-4
% total-h-count
H0             total-h-count-0
H1             total-h-count-1
H2             total-h-count-2
H3             total-h-count-3
% formal charge
+0             neutral
+1             cationic+1
-1             anionic-1
% aromatic/aliphatic
a              aromatic
A              aliphatic

This option also has the corresponding string token.

Example: smarty --basetypes=examples/AlkEtOH/atomtypes/basetypes.smarts --initialtypes=examples/AlkEtOH/atomtypes/basetypes.smarts --decorators=examples/AlkEtOH/atomtypes/new-decorators.smarts --molecules=examples/AlkEtOH/molecules/test_filt1_tripos.mol2 --reference=examples/AlkEtOH/molecules/test_filt1_ff.mol2 --iterations 1000 --temperature=0.00001

Newly proposed atom types are added to the end of the list. After a new atom type is proposed, all molecules are reparameterized using the new set of atom types. Atom type matching proceeds by trying to see if each SMARTS match can be applied working from top to bottom of the list. This means the atom type list is hierarchical, with more general types appearing at the top of the list and more specific subtypes appearing at the bottom.

If a proposed type matches zero atoms, the RJMCMC move is rejected.

Currently, the acceptance criteria does not include the full Metropolis-Hastings acceptance criteria that would include the reverse probability. This needs to be added in.

The SMIRFF forcefield format is available in sample form under data/forcefield, and is handled by forcefield.py. An example comparing SMIRFF versus AMBER energies for the parm@frosst forcefield is provided under examples/SMIRFF_comparison, where two scripts can compare energies for a single molecule or for the entire AlkEthOH set. Note that two forcefields are currently available in this format, Fross_AlkEtOH.ffxml, the parm@frosst forcefield as it should have been for this set, and Frosst_AlkEtOH_parmAtFrosst.ffxml, the forcefield as it was actually implemented (containing several bugs as noted in the file itself).

It can also be of interest to know what SMIRFF parameters would be applied to particular molecules. Utility functionality for this is provided under forcefield_labeler.py, which has generally similar structure to forcefield.py but instead of providing OpenMM systems with parameters, it can be applied to specific molecules and returns information about what parameters would be applied.

[1] Green PJ. Reversible jump Markov chain Monte Carlo computation and Bayesian model determination. Biometrika 82:711, 1995. http://dx.doi.org/10.1093/biomet/82.4.711