Extension of the CHARMM general force field to sulfonyl‐containing compounds and its utility in biomolecular simulations

Abstract

Presented is an extension of the CHARMM General force field (CGenFF) to enable the modeling of sulfonyl-containing compounds. Model compounds containing chemical moieties such as sulfone, sulfonamide, sulfonate and sulfamate were used as the basis for the parameter optimization. Targeting high-level quantum mechanical and experimental crystal data, the new parameters were optimized in a hierarchical fashion designed to maintain compatibility with the remainder of the CHARMM additive force field. The optimized parameters satisfactorily reproduced equilibrium geometries, vibrational frequencies, interactions with water, gas phase dipole moments and dihedral potential energy scans. Validation involved both crystalline and liquid phase calculations showing the newly developed parameters to satisfactorily reproduce experimental unit cell geometries, crystal intramolecular geometries and pure solvent densities. The force field was subsequently applied to study conformational preference of a sulfonamide based peptide system. Good agreement with experimental IR/NMR data further validated the newly developed CGenFF parameters as a tool to investigate the dynamic behavior of sulfonyl groups in a biological environment. CGenFF now covers sulfonyl group containing moieties allowing for modeling and simulation of sulfonyl-containing compounds in the context of biomolecular systems including compounds of medicinal interest.

CHARMM additive and polarizable force fields for biophysics and computer-aided drug design

“…Additionally, a targeted effort was made to cover a variety of sulfonyl-containing functional groups, including sulfonamides, sulfones, sulfoxides, anionic sulfonates, sulfonic esters, sulfamates and neutral organic sulfonates. 83 As the coverage gradually expanded, regular updates were made available, causing CGenFF to adapt a separate release cycle from the CHARMM biomolecular parameter sets. It should be emphasized that this does not imply it is a separate force field; instead, CGenFF can be considered an evolving part of CHARMM36 that is fully compatible with its biomolecular counterparts.…”

Specific effects of monovalent counterions on the structural and interfacial properties of dodecyl sulfate monolayers

“…All monolayer simulations were performed at T = 300 K using the LAMMPS simulation package 48 with the CHARMM force field 49,50 for the description of both inter-and intra-molecular interactions of the DS − and the various counterions 51,52 . The TIP3P water model 53 , which was modified for the CHARMM forcefield 54 , was used to describe interactions involving water.…”

Molecular Mechanics

“…[12, 110–112] Similarly, the proximity between atoms during an MD simulation can be correlated to data from Nuclear Overhauser Effect (NOE)-based NMR techniques such as NOESY and ROESY for the purpose of validating and fine-tuning force fields. [113] Additionally, NOE data can be used as target data in a similar fashion as crystallographic data[114–121] (see subsection 4.2.1). Finally, spin-relaxation data can be correlated to the effective correlation time in simulations.…”

“…OPLS-AA,[163–165] whose optimizations emphasized condensed phase properties of small molecules, has been extended to cover a diverse set of small molecule model compounds and may be a good choice, though atom type assignment must be done by hand (although there exists a commercial implementation of OPLS-AA with atom typing functionality[166]). CHARMM has been extended with the CHARMM General Force Field (CGenFF), which covers a wide range of chemical groups present in biomolecules and drug-like molecules including a large number of heterocyclic scaffolds,[80, 113] and a web interface for automatic atom typing and assignment of parameters and charges by analogy has recently been published. [74, 75] Finally, the GROMOS force field atom type palette, which derives from parameters for biopolymers, also provides a reasonable amount of diversity for the construction of force field models of small molecules.…”