Color Force Field

The chemical force field can be used to measure chemical complementarity, and to refine shape based superpositions based on chemical similarity. The CFF is composed of SMARTS rules that determine chemical centers, plus rules to determine how such centers interact.

Default Color Files

Two color force fields, ImplicitMillsDean and ExplicitMillsDean, are built into ROCS. Both these force fields define six similar TYPE color force-fields. The types are hydrogen-bond donors, hydrogen-bond acceptors, hydrophobes, anions, cations, and rings. The ImplicitMillsDean force field is recommended.

ImplicitMillsDean includes a simple pKa model that assumes pH=7. It defines cations, anions, donors and acceptors in such a way that they will be assigned the appropriate value independent of the protonation state in the dbase or query file. For example, if a molecule contains a carboxylate, ImplicitMillsDean will consider it an anionic center independent of whether it is protonated or deprotonated in the dbase file. This is convenient for searching databases which have not had careful curation of their protonation states. The ExplicitMillsDean file has a similar overall interaction model, however, it does not include a pKa model. It interprets the protonation and charge state of each molecule exactly as it is in the database. Thus, if a sulfate is protonated and neutral, it will not consider it an anion.

The hydrogen-bond models in both ImplicitMillsDean and ExplicitMillsDean are extensions of the original model presented by Mills and Dean ([Mills-Dean-1996]). They both have donors and acceptors segregated into strong, moderate and weak categories.

Color File Format

As an alternative to the built-in force fields, the user can define a new color force field using the format described in this section. The following is a simplified example of a color force field specification.

DEFINE hetero [#7,#8,#15,#16]
DEFINE notNearHetero [!#1;!$($hetero);!$(\*[$hetero])]
TYPE donor
TYPE acceptor
TYPE rings
TYPE positive
TYPE negative
TYPE structural
PATTERN donor [$hetero;H]
PATTERN acceptor [#8&!$(\*~N~[OD1]),#7&H0;!$([D4]);!$([D3]-\*=,:[$hetero])]
PATTERN rings [R]~1~[R]~[R]~[R]1
PATTERN rings [R]~1~[R]~[R]~[R]~[R]1
PATTERN rings [R]~1~[R]~[R]~[R]~[R]~[R]1
PATTERN rings [R]~1~[R]~[R]~[R]~[R]~[R]~[R]1
PATTERN positive [+,$([N;!$(\*-\*=O)])]
PATTERN negative [-]
PATTERN negative [OD1+0]-[!#7D3]~[OD1+0]
PATTERN negative [OD1+0]-[!#7D4](~[OD1+0])~[OD1+0]
PATTERN structural [$notNearHetero]
INTERACTION donor donor attractive gaussian weight=1.0 radius=1.0
INTERACTION acceptor acceptor attractive gaussian weight=1.0 radius=1.0
INTERACTION rings rings attractive gaussian weight=1.0 radius=1.0
INTERACTION positive positive attractive gaussian weight=1.0 radius=1.0
INTERACTION negative negative attractive gaussian weight=1.0 radius=1.0
INTERACTION structural structural attractive gaussian weight=1.0 radius=1.0

There are four basic keywords in a cff file: DEFINE, TYPE, PATTERN, and INTERACTION. The TYPE field can be any user-defined term. TYPES can be any user-specified string such as “donor”, “acceptor”, “lipophilic anion” etc. The PATTERN keyword is used to associate SMARTS patterns with these types. There is no restriction on the number of patterns that can be associated with a user defined type. The position in Cartesian space of the PATTERN is taken as the average of the coordinates of the atoms that match the SMARTS pattern. If the desired location of the PATTERN is on a single atom of a larger SMARTS pattern recursive SMARTS (written as ‘[$(SMARTS)]’ can be used to this effect. Only the first atom in a recursive SMARTS pattern ‘matches’ the molecule, and the rest of the SMARTS pattern defines an environment. By writing a SMARTS pattern in recursive notation the location of the PATTERN will be taken as the atomic position of the first matching atom in the pattern. In order to simplify both reading and writing SMARTS, intermediate SMARTS can be associated with words using the DEFINE keyword. Once defined, these words can then be used as atom primitives in subsequent SMARTS patterns with the $ prefix (see “DEFINE hetero” and “PATTERN donor” above).

Interactions between types are associated with the INTERACTION keyword. Two user-defined types must be listed, and whether their interaction is attractive or repulsive. The height and radius can be modified by keywords WEIGHT and RADIUS. At present, the only alternative to a Gaussian decay is invoked by the DISCRETE keyword. A discrete interaction contributes all of WEIGHT if the inter-type distance is less than RADIUS, or zero. Since it is not differentiable it makes no contribution to optimization (i.e. because the gradient of a DISCRETE function is 0 or infinite).