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By Franck Chevalier


Molecular recognition is rarely a two-body protein-ligand problem, as it often involves the dynamic interplay of multiple molecules that together control the binding process. Myo-inositol monophosphatase (IMPase), a drug target for bipolar disorder, depends on 3 Mg2+ ions as cofactor for its catalytic activity. Although the crystallographic pose of the pre-catalytic complex is well characterized, the binding process by which substrate, cofactor and protein cooperate is essentially unknown. Here, we have characterized cofactor and substrate cooperative binding by means of large-scale molecular dynamics. Our study showed the first and second Mg2+ ions identify the binding pocket with fast kinetics whereas the third ion presents a much higher energy barrier. Substrate binding can occur in cooperation with cofactor, or alone to a binary or ternary cofactor-IMPase complex, although the last scenario occurs several orders of magnitude faster. Our atomic description of the three-body mechanism offers a particularly challenging example of pathway reconstruction, and may prove particularly useful in realistic contexts where water, ions, cofactors or other entities cooperate and modulate the binding process.
In all in-silico binding analyses, full kinetic and thermodynamic data were obtained by performing free-ligand binding, all-atom molecular dynamics simulations with the ACEMD molecular dynamics software and anlyzed with HTMD.

We have fully characterized substrate and cofactor binding prior to the catalytic event.
We have also provided an atomic-level description of substrate and cofactor cooperation and binding.
Large-scale HTMD has been used and been able to recapitulate the binding events of Mg ions and natural substrate at IMPase, and we identified structures close to the X-ray solutions.

N Ferruz, G Tresadern, A Pineda-Lucena, G De Fabritiis, Multibody cofactor and substrate molecular recognition in the myo-inositol monophosphatase enzyme, Scientific Reports 2016

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