Macrocyclic spiroimine phycotoxins constitute a growing class of structurally related marine neurotoxins contaminating shellfish. Most of them are strong antagonists of nicotinic acetylcholine receptors (nAChRs). During recent years this field has witnessed important developments with regard to chemical synthesis, X-ray crystallography, electrophysiology, detection methods and molecular modelling. In this study, the conformational flexibility of representative cyclic imine phycotoxins (gymnodimines, spirolides, pinnatoxins, pteriatoxins, spiro-prorocentrimine and prorocentrolides) was evaluated using long-timescale all-atom molecular dynamics simulations. As parameters for imine and iminium groups were missing from the standard OPLS-AA force field, the required charges and bonded parameters were generated using a protocol developed in our team [1]. The initial conformations were taken from the available X-ray structures [2], from our previous docking studies [3] or generated from scratch. A special attention was paid to the more flexible toxins presenting an amino-ketone system instead of the imine ring: spirolides E and F, pinnatoxin A amino ketone [4]. This study confirmed our previous data [5] showing that these macrocyclic compounds feature several rigid building blocks connected by flexible linkers, and gave access to regions in the conformational space that were previously unexplored.This study allows a better understanding of the conformational flexibility of these phycotoxins in solution. Careful analysis of the hydration sites identified here will provide additional information regarding the thermodynamics of the interaction between these toxins and their main target, nAChRs, which ultimately will lead to the design of new derivatives with improved biological activities, subtype selectivities and pharmacological properties.1. Beckstein and Iorga, J. Comput. Aided Mol. Des., 2012, 26, 6352. Bourne et al., Proc. Natl. Acad. Sci. USA, 2010, 107, 60763. Ar�oz et al., J. Am. Chem. Soc., 2011, 133, 104994. Jackson et al., J. Org. Chem., 2012, 77, 104355. Ar�oz et al., Toxicon, 2013, 75, 218

Conformational flexibility of cyclic imine phycotoxins revealed by long-timescale molecular dynamics simulations

247th National Meeting (2014)

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