Like last year, Schrodinger is hosting webinars regarding new application developments, one ever week. Here is the schedule for those who may be interested. Registration is easy. Our group is thinking of doing most of them, especially the docking sessions.
They did the QM polarized docking module seminar today. Current docking routines often fail to give good results because of lack of treatement of polarization effects, which can be ultimately traced back to the charges on the ligand atoms. Polarization effects are crucial in calculating transition states for enzyme reactions for example.
Charges on ligand atoms constitute a big topic in themselves, and many methods have been developed to get accurate charges, including semi-empirical and ab-initio methods. Probably the best method I know involves calculating the electrostatic potential and then fitting those charges to the atoms which reproduce the potential the best, a method which I believe was developed by the late Peter Kollman (whose papers are still getting published five years after he passed away). Charges on atoms forming h-bonds for example can greatly change h-bond stabilization energies.
Cute electrostatic potential factoid: ESP studies can often reveal features of molecules that are not obvious upon inspection. For example, the ESP potential well is much deeper for the N3 of cytosine than the O8. 'Inspection' may suggest that it's the O8 that is the most nucleophilic, but experiment shows that alkylation and protonation take place on N3 as suggested by the ESP
In any case, the Schrodinger group uses poses from regular docking with their module Glide, and then uses a program called QSite to do a single point energy calculation using a good basis set, that endows the ligand atoms with charges. The poses are then redocked. Using this methodology, they were able to get good docked poses for many proteins that were outliers with regular docking (RMSD>2 A). Top of the outlier list was HIV-1 protease, and I suspect that the hydrophobic nature of the site can raise special issues. Regular Glide probably cannot find the correct pose for compounds in this site because many compounds bind tightly to the protease purely on the basis of the hydrophobic effect, without having any significant hydrogen bonding.
Reference: "Importance of Accurate Charges in Molecular Docking: Quantum Mechanical/Molecular Mechanical (QM/MM) Approach"- AE Cho, V Guallar, BJ Berne, R Friesner - Journal of Computational Chemistry, 2005
Macrocycles, flexibility and biological activity: A tortuous pairing
6 hours ago in The Curious Wavefunction