Rewarding Cancer Research

Real-world observable physical and chemical characteristics are increasingly being calculated from the 3D structures of biomolecules. Methods for calculating pKa values, binding constants of ligands, and changes in protein stability are readily available, but often the limiting step in computational biology is the conversion of PDB structures into formats ready for use with biomolecular simulation software. The continued sophistication and integration of biomolecular simulation methods for systemsand genome-wide studies requires a fast, robust, physically realistic and standardized protocol for preparing macromolecular structures for biophysical algorithms. As described previously, the PDB2PQR web server addresses this need for electrostatic field calculations (Dolinsky et al., Nucleic Acids Research, 32, W665–W667, 2004). Here we report the significantly expanded PDB2PQR that includes the following features: robust standalone command line support, improved pKa estimation via the PROPKA framework, ligand parameterization via PEOE_PB charge methodology, expanded set of force fields and easily incorporated user-defined parameters via XML input files, and improvement of atom addition and optimization code. These features are available through a new web interface (http:// pdb2pqr.sourceforge.net/), which offers users a wide range of options for PDB file conversion, modification and parameterization. INTRODUCTION Due to the importance of electrostatic interactions in biomolecular systems, a variety of computational methods have been developed for evaluating electrostatic forces and energies [see (1–6) and references therein]. Typical computational electrostatics methods for biomolecular systems can be loosely grouped into two categories: ‘explicit solvent’ methods, which treat solvent molecules in full molecular detail, and ‘implicit solvent’ methods, which include solvent–solute interactions in averaged or continuum fashion. Implicit solvent methods are, by definition, limited in detail and therefore lack the atomic-scale accuracy of their explicit solvent counterparts. However, implicit solvent methods have gained increasing popularity, in part due to their elimination of the extensive sampling of solvent configurations required with explicit models (1,3–7). The basic ingredients of an implicit solvent electrostatics calculation are environmental parameters such as temperature, solvent dielectric and ionic strength; biomolecular atomic coordinates; and parameters for atomic charges and radii. While the environmental parameters are relatively straightforward to specify, the remaining two ingredients can often be difficult to supply. In particular, most biomolecular structures in the Protein Data Bank (PDB) (8) do not contain hydrogen atoms, and many are also missing a fraction of the heavy atom coordinates. The addition of hydrogens and the reconstruction of these missing coordinates is not a trivial process; electrostatic properties obtained from the ‘repaired’ structures can often be very sensitive to the manner in which missing atoms are added and protonation states are assigned (9,10). Furthermore, inconsistent atomic nomenclature and other *To whom correspondence should be addressed. Tel: þ1-314-362-2040; Fax: þ1-314-362-0234; Email: [email protected]