NDLI: Conformational analysis of a polyconjugated protein-binding ligand by joint quantum chemistry and polarizable molecular mechanics. Addressing the issues of anisotropy, conjugation, polarization, and multipole transferability

Content Provider	Springer Nature Link
Author	Goldwaser, Elodie Courcy, Beit Demange, Luc Garbay, Christiane Raynaud, Françoise Hadj Slimane, Reda Piquemal, Jean Philip Gresh, had
Copyright Year	2014
Abstract	We investigate the conformational properties of a potent inhibitor of neuropilin-1, a protein involved in cancer processes and macular degeneration. This inhibitor consists of four aromatic/conjugated fragments: a benzimidazole, a methylbenzene, a carboxythiourea, and a benzene-linker dioxane, and these fragments are all linked together by conjugated bonds. The calculations use the SIBFA polarizable molecular mechanics procedure. Prior to docking simulations, it is essential to ensure that variations in the ligand conformational energy upon rotations around its six main-chain torsional bonds are correctly represented (as compared to high-level ab initio quantum chemistry, QC). This is done in two successive calibration stages and one validation stage. In the latter, the minima identified following independent stepwise variations of each of the six main-chain torsion angles are used as starting points for energy minimization of all the torsion angles simultaneously. Single-point QC calculations of the minimized structures are then done to compare their relative energies ΔE conf to the SIBFA ones. We compare three different methods of deriving the multipoles and polarizabilities of the central, most critical moiety of the inhibitor: carboxythiourea (CTU). The representation that gives the best agreement with QC is the one that includes the effects of the mutual polarization energy E pol between the amide and thioamide moieties. This again highlights the critical role of this contribution. The implications and perspectives of these findings are discussed.
Starting Page	1
Ending Page	24
Page Count	24
File Format	PDF
ISSN	16102940
Journal	Journal of Molecular Modeling
Volume Number	20
Issue Number	11
e-ISSN	09485023
Language	English
Publisher	Springer Berlin Heidelberg
Publisher Date	2014-11-01
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Polarizable force fields Multipoles Conjugation Computer Applications in Chemistry Molecular Medicine Computer Application in Life Sciences Characterization and Evaluation of Materials Theoretical and Computational Chemistry
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Physical and Theoretical Chemistry Computational Theory and Mathematics Catalysis Inorganic Chemistry Computer Science Applications

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