ORIGINAL PAPER Ab initio parameterization of YFF1, a universal force field for drug-design applications Olexandr Ya Yakovenko & Yvonne Y. Li & Alexander A. Oliferenko & Ganna M. Vashchenko & Volodymyr G. Bdzhola & Steven J. M. Jones Received: 22 July 2010 / Accepted: 14 April 2011 / Published online: 12 May 2011 # Springer-Verlag 2011 Abstract The YFF1 is a new universal molecular mechanic force field designed for drug discovery purposes. The electrostatic part of YFF1 has already been parameterized to reproduce ab initio calculated dipole and quadrupole moments. Now we report a parameterization of the van der Waals interactions (vdW) for the same atom types that were previously defined. The 6–12 Lennard-Jones potential terms were parameterized against homodimerization energies calculated at the MP2/6-31 G* level of theory. The Boys- Bernardi counterpoise correction was employed to account for the basis-set superposition error. As a source of structural information we used about 2,400 neutral compounds from the ZINC2007 database. About 6,600 homodimeric config- urations were generated from this dataset. A special “closure” procedure was designed to accelerate the param- eters fitting. As a result, dimerization energies of small organic compounds are reproduced with an average un- signed error of 1.1 kcal mol -1 . Although the primary goal of this work was to parameterize nonbonded interactions, bonded parameters were also derived, by fitting to PM6 semiempirically optimized geometries of approximately 20,000 compounds. Keywords Force fields . Parameterization . Quantum chemical calculations Introduction The common approach in biomolecular modeling is using molecular mechanical force fields (FF): sets of prede- fined functions and parameters derived from experimen- tal data or high level ab initio calculations. There are a lot of FFs that differs in parameterization sources, interaction modeling functions and consequently field of applicability. For instance, the MM2 parameterized to reproduce conformational energies of hydrocarbons was then ex- tended (MM3, MM4) to work with many other organic molecules [1–4], OPLS [5, 6] was fitted against enthalpies of vaporization. GROMOS [7] is designed for modeling biomolecules in aqueous solutions. DRF90 [8] attempts to introduce polarization in the form of effective polarizabil- ity tensors, while AMBER [9] does the same with a point charge flow approach, and CHARMM with the Drude oscillator model [10]. However, it is difficult to guarantee a reasonable accuracy of a FF for problems beyond its Electronic supplementary material The online version of this article (doi:10.1007/s00894-011-1095-3) contains supplementary material, which is available to authorized users. O. Yakovenko (*) : Y. Y. Li : S. J. M. Jones Genome Sciences Centre, BC Cancer Agency, Suite 100 570 West 7th Avenue, Vancouver, British Columbia, Canada e-mail: ayakovenko@bcgsc.ca O. Yakovenko e-mail: yakovenko.alexander@gmail.com A. A. Oliferenko Department of Chemistry, University of Florida, Gainesville, FL 32611, USA V. G. Bdzhola Institute of Molecular Biology and Genetics of National Academy of Sciences of Ukraine, 150 Zabolotny str, Kyiv 03143, Ukraine G. M. Vashchenko Department of Biochemistry and Molecular Biology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia, Canada J Mol Model (2012) 18:663–673 DOI 10.1007/s00894-011-1095-3