VConf is a powerful and flexible conformational search application which processes an SD file of drug-like compounds containing an initial 2D or 3D conformation of each molecule. It provides for two major modes of operation:
- 2D to 3D with multiple ring conformations
In “prep” mode Vconf quickly transforms a 2D or low-grade 3D starting conformation into several high-quality 3D structures with various conformations of any flexible rings that may be present. This mode is useful for preparing molecules for subsequent calculations, like docking, which vary only bond torsions.
- Full conformational search
In “search” mode, Vconf carries out the “prep” step described above, and then executes a Tork conformational search in all degrees of freedom. Time requirements vary depending upon the complexity of the molecule and the options selected by the user.
User Options
Command-line options provide detailed user control, including:
- list of atoms, if any, whose positions will be locked to their input coordinates
- maximum number of output structures
- energy cutoff for filtering out high energy structures
- distance tolerance for filtering repeat structures
- whether constraints should be imposed on the chirality of stereo centers and on cis/trans conformations at double bonds
- how the chirality of a atom should be determined; i.e. by the parity field in the atom block, the stereo bond information in the bond block, or the coordinates of the input structure. More than one method can be specified
- how valence is detected; i.e. based on formal charges specified in input SDfile, or on the assumption that all intended hydrogens are present in the input SDfile
- the distant dependent dielectric constant coefficient
How VConf Works
The method begins by removing small disconnected molecular fragments from the input molecule and adding missing hydrogens or formal charges. Vconf then detects ring systems and draws multiple low-energy conformations of each ring system from a dynamic ring database or uses Tork to quickly build conformations of rings not already in the database. Multiple starting conformations of the molecule are then built around these rings and relaxed by a brief Monte Carlo run followed by energy minimization. In “prep” mode, the calculation is stopped at this point. In “search” mode, the resulting structures are used to initiate Tork searches to generate a range of low-energy conformations. As described in the first citation below, Tork uses normal modes in internal coordinates to efficiently identify productive directions for the conformational search. The conformations thus generated are checked for correct chirality, and cis/trans conformations at double bonds. Finally, repeat conformations are eliminated, correcting for symmetries, and the successful conformations are written to output. Energies are based upon a tuned version of the Dreiding force field, with VeraChem’s partial atomic charges (see VCharge) and a distance-dependent dielectric model.
Windows User-Interface
The MS Windows version of Vconf includes a convenient graphical user interface that facilitates assigning parameters, running Vconf, and viewing its results. The interface brings together Vconf, our molecular display program VDisplay, and helpful Vconf support utilities, as shown in the following screen-shots. (Click images for full-sized views)
Vconf version 1.0 for Microsoft Windows® including a graphical user interface and Linux.
REFERENCES
Main Citations
Chang, C.-E. and M. K. Gilson (2003). “Tork: Conformational analysis method for molecules and complexes.” Journal of Computational Chemistry 24(16): 1987-1998. DOI: 10.1002/jcc.10325
Background Citations
Chen, W., J. Huang, and M. K. Gilson (2004). “Identification of symmetries in molecules and complexes.” Journal of Chemical Information and Computer Sciences 44(4): 1301-1313. DOI: 10.1021/ci049966a
David, L., R. Luo, and M. K. Gilson (2001). “Ligand-receptor docking with the Mining Minima optimizer.” J. Comput. Aided Mol. Des. 15: 157-171. DOI: 10.1023/A:1008128723048
Figueras, J. (1996). “Ring perception using breadth-first search.” Journal of Chemical Information and Computer Sciences 36(5): 986-991. DOI: 10.1021/ci960013p
Gilson, M. K., H. S. R. Gilson, and M. J. Potter (2003). “Fast assignment of accurate partial atomic charges: An electronegativity equalization method that accounts for alternate resonance forms.” J. Chem. Inf. Comput. Sci. 43: 1982-1997. DOI: 10.1021/ci034148o
Kairys, V. and M. K. Gilson (2002). “Enhanced docking with the mining minima optimizer: acceleration and side-chain flexibility.” J. Comput. Chem. 23: 1656-1670. DOI: 10.1002/jcc.10168
Mayo, S. L., B. D. Olafson, W. A. Goddard III (1990). “DREIDING: A generic force field for molecular simulations.” J. Phys. Chem. 94: 8897-8909. DOI: 10.1021/j100389a010
