Structural Survey of Zinc-Containing Proteins and Development of the Zinc AMBER Force Field (ZAFF)

Currently the Protein Data Bank (PDB) contains over 25 000 structures that contain a metal ion including Na, Mg, K, Ca, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Pd, Ag, Cd, Ir, Pt, Au, and Hg. In general, carrying out classical molecular dynamics (MD) simulations of metalloproteins is a convoluted and time-consuming process. Herein, we describe MCPB (Metal Center Parameter Builder), which allows one to conveniently and rapidly incorporate metal ions using the bonded plus electrostatics model (Hoops et al. J. Am. Chem. Soc. 1991, 113, 8262−8270) into the AMBER force field (FF). MCPB was used to develop a zinc FF, ZAFF, which is compatible with the existing AMBER FFs. The PDB was mined for all Zn-containing structures with most being tetrahedrally bound. The most abundant primary shell ligand combinations were extracted, and FFs were created. These include Zn bound to CCCC, CCCH, CCHH, CHHH, HHHH, HHHO, HHOO, HOOO, HHHD, and HHDD (O = water and the remaining are 1-letter amino acid codes). Bond and angle force constants and RESP charges were obtained from B3LYP/6-31G* calculations of model structures from the various primary shell combinations. MCPB and ZAFF can be used to create FFs for MD simulations of metalloproteins to study enzyme catalysis, drug design, and metalloprotein crystal refinement.