title: Improved QM/MM Linear-Interaction Energy Model for Substrate Recognition in Zinc-Containing Metalloenzymes.
abstract: One of the essential challenges in the description of receptor-drug interactions in the presence of various polyvalent cations (such as zinc, magnesium, or iron) is the accurate assessment of the electronic effects due to cofactor binding. The effects can range from partial electronic polarization of the proximal atoms in a receptor and bound substrate to long-range effects related to partial charge transfer and electronic delocalization effects between the cofactor and the drug. Here, we examine the role of the explicit account for electronic effects for a panel of small-molecule inhibitors binding to the zinc-aminopeptidase PfA-M1, an essential target for antimalarial drug development. Our study on PfA-M1:inhibitor interactions at the QM level reveals that the partial charge and proton transfer due to bound zinc ion are important mechanisms in the inhibitors' recognition and catalysis. The combination of classical MD simulations with a posteriori QM/MM corrections with novel DFTB parameters for the zinc cation and the linear-interaction energy (LIE) approach offers by far the most accurate estimates for the PfA-M1:inhibitor binding affinities, opening the door for future inhibitor design.
authors.affiliation: Computational Biology and Biomolecular Dynamics Laboratory, Center for Protein Studies, Faculty of Biology, University of Havana , Havana, Cuba.|Centre for Molecular Simulations and Department of Biological Sciences, University of Calgary , 2500 University Drive, BI-449, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Williams E
authors.initials: WE
authors.lastname: Miranda
authors.affiliation: Centre for Molecular Simulations and Department of Biological Sciences, University of Calgary , 2500 University Drive, BI-449, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Van A
authors.initials: VA
authors.lastname: Ngo
authors.affiliation: Computational Biology and Biomolecular Dynamics Laboratory, Center for Protein Studies, Faculty of Biology, University of Havana , Havana, Cuba.
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Valiente
authors.affiliation: Centre for Molecular Simulations and Department of Biological Sciences, University of Calgary , 2500 University Drive, BI-449, Calgary, Alberta T2N 1N4, Canada.
authors.forename: Sergei Yu
authors.initials: SY
authors.lastname: Noskov
mesh_terms: D000626:Aminopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D002384:Catalysis; D020134:Catalytic Domain; D003198:Computer Simulation; D015195:Drug Design; D004560:Electricity; D016014:Linear Models; D008667:Metalloproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D008958:Models, Molecular; D011522:Protons; D011789:Quantum Theory; D013237:Stereoisomerism; D013379:Substrate Specificity; D015032:Zinc / Q000378:metabolism*
chemical_list: D000962:Antimalarials; D008667:Metalloproteins; D011522:Protons; D000626:Aminopeptidases; D015032:Zinc