The influence of variations of ligand protonation and tautomerism on protein-ligand recognition and binding energy landscape.
We investigate the influence of variations of ligand protonation and tautomeric states on the protein-ligand binding energy landscape by applying the concept of structural consensus. In docking simulations, allowing full flexibility of the ligand, we explore whether the native binding mode could be successfully recovered using a non-native ligand protonation state. Here, we consider three proteins, dihydrofolate reductase, transketolase, and alpha-trichosanthin, complexed with ligands having multiple tautomeric forms. We find that for the majority of protonation and tautomeric states the native binding mode can be recovered without a great loss of accuracy.
Todorov
Nikolay P
NP
De Novo Pharmaceuticals Ltd., Vision Park, Histon, Cambridge CB49ZR, United Kingdom. nikolay.todorov@denovopharma.com
Monthoux
Philippe H
PH
Alberts
Ian L
IL
D018360:Crystallography, X-Ray; D008024:Ligands; D008958:Models, Molecular; D011506:Proteins / Q000378:metabolism*; D011522:Protons; D013237:Stereoisomerism
D008024:Ligands; D011506:Proteins; D011522:Protons