Naslov
A rush to explore protein–ligand electrostatic interaction energy with Charger

Autori
Vuković, Vedran ; Leduc, Theo ; Jelić-Matošević, Zoe ; Didierjean, Claude ; Favier, Frédérique ; Guillot, Benoît ; Jelsch, Christian

Izvornik
Acta crystallographica. Section D, Structural biology (2059-7983) 77 (2021), 10; 1292-1304

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

Ključne riječi
electrostatics ; polarization ; interaction energy ; Hansen–Coppens model ; protein–ligand interactions ; Charger

Sažetak
The mutual penetration of electron densities between two interacting molecules complicates the computation of an accurate electrostatic interaction energy based on a pseudo-atom representation of electron densities. The numerical exact potential and multipole moment (nEP/MM) method is time-consuming since it performs a 3D integration to obtain the electrostatic energy at short interaction distances. Nguyen et al. [(2018), Acta Cryst. A74, 524–536] recently reported a fully analytical computation of the electrostatic interaction energy (aEP/MM). This method performs much faster than nEP/MM (up to two orders of magnitude) and remains highly accurate. A new program library, Charger, contains an implementation of the aEP/MM method. Charger has been incorporated into the MoProViewer software. Benchmark tests on a series of small molecules containing only C, H, N and O atoms show the efficiency of Charger in terms of execution time and accuracy. Charger is also powerful in a study of electrostatic symbiosis between a protein and a ligand. It determines reliable protein–ligand interaction energies even when both contain S atoms. It easily estimates the individual contribution of every residue to the total protein–ligand electrostatic binding energy. Glutathione transferase (GST) in complex with a benzophenone ligand was studied due to the availability of both structural and thermodynamic data. The resulting analysis highlights not only the residues that stabilize the ligand but also those that hinder ligand binding from an electrostatic point of view. This offers new perspectives in the search for mutations to improve the interaction between the two partners. A proposed mutation would improve ligand binding to GST by removing an electrostatic obstacle, rather than by the traditional increase in the number of favourable contacts.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija

POVEZANOST RADA