New Binding Mode of SLURP Protein to a7 Nicotinic Acetylcholine Receptor Revealed by Computer Simulations

Andrey V. Golovin, Igor D. Diankin, Arthur O. Zalevsky, Denis S. Kudryavtsev, Victor I. Tsetlin



SLURP-1 is a member of three-finger toxin-like proteins. Their characteristic feature is a set of three beta strands extruding from hydrophobic core stabilized by disulfide bonds. Each beta-strand carries a flexible loop, which is responsible for recognition. SLURP-1 was recently shown to act as an endogenous growth regulator of keratinocytes and tumor suppressor by reducing cell migration and invasion by antagonizing the pro-malignant effects of nicotine. This effect is achieved through allosteric interaction with alpha7 nicotinic acetylcholine receptors (alpha-7 nAChRs) in an antagonist-like manner. Moreover, this interaction is unaffected by several well-known agents specifically alpha-bungarotoxin.

In this work, we carry out the conformational analysis of the SLURP-1 by a microsecond-long full-atom explicit solvent molecular dynamics simulations followed by clustering, to identify representative states. To achieve this timescale we employed a GPU-accelerated version of GROMACS modeling package. To avoid human bias in clustering we used a non-parametric clustering algorithm Affinity Propagation adapted for biomolecules and HPC environments. Then, we applied protein-protein molecular docking of the ten most massive clusters to alpha7-nAChRs in order to test if structural variability can affect binding. Docking simulations revealed the unusual binding mode of one of the minor SLURP-1 conformations.



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