Baltimore, MD, 26 April, 2019

In ongoing efforts to improve the coverage of the CGenFF program, version 2.3.0 of the CGenFF program improves support for a variety of molecules via explicit parametrization of the molecules outlined below and features improvements for halogen-protein interactions.

Molecules explicitly parametrized
The functional groups in these molecules were previously accessible in CGenFF based on analogy to related functional groups. Now, after explicitly parametrizing and validating the parameters for these molecules and associated functional groups, CGenFF provides more accurate treatment and a decrease in the CGenFF penalties for these compounds.

▪ 1H-tetrazole
▪ 5-Methyl-1H-tetrazole
▪ 5-Ethyl-1H-tetrazole

▪ 2-Oxetanone
▪ 3-Oxetanone

▪ Ammonium
▪ Dimethylammonium
▪ Trimethylammonium
Note: Protonated amine parameters were previously based on methylammonium. With explicit optimization of the secondary and tertiary amines, CGenFF penalties are smaller and performance is improved. The charged nature of these groups makes the impact of subtle changes in the charge distribution relatively small given the dominant contribution of the monopole to interactions with the environment.

▪ 1-butyne
▪ 1-pentyne
▪ 1-hexyne
▪ 1-heptyne
▪ 1-octyne
▪ But-1-ene-3-yne
Note: Alkyne parameters were previously based on ethene and propene. Extension to longer alkynes and the ene/yne combination validates the parameters and leads to improved treatment of the intramolecular parameters.

Improved halogen –protein interactions
Quantum mechanical calculations on chloro- and bromobenzene with model compounds representative of protein functional groups were used as target data to optimize atom-pair specific Lennard-Jones parameters for selected atoms in the model compounds. Application of the parameters in MD simulations of eight ligand-protein systems showed systematic improvement in the interaction geometries.
For more details see Lin, F.-Y. and MacKerell Jr., A.D., “Improved Modeling of Halogenated Ligand-Protein Interactions using the Drude Polarizable and CHARMM Additive Empirical Force Fields,” Journal of Chemical Information and Modeling, ASAP article 2018, 10.1021/acs.jcim.8b00616, NIHMSID 997173.

About SilcsBio, LLC: SilcsBio started operations in April 2013 based on licensed intellectual property developed by Dr. Alexander D. MacKerell, Jr at the University of Maryland, Baltimore where he is the Grollman-Glick Professor of Pharmaceutical Sciences and Director of the Computer-Aided Drug Design Center. SilcsBio offers commercial software and services based on their software tools for structure-based drug design and has customers in the US, UK, Japan, and Europe. The company is headquartered at Spark-Baltimore located at 8 Market Place, Suite 300, Baltimore, MD 21202.

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