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PrimaryOdors.org molecular docker.
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pKa shifts of nitrogenous aromatic heterocycles. #273

Open electronicsbyjulie opened 1 year ago

electronicsbyjulie commented 1 year ago

It is known that an aspartate hydrogen bonded to a histidine increases the latter's pKa causing it to be ionized at biological pH (citation necessary). Might aspartate and glutamate side chains have a similar effect on pyrazines etc.? For sure, the identity of His as an uncharged hydrophobic vs. charged hydrophilic side chain should be computed depending on its surroundings, for purposes of not only docking and scoring but also best-binding and tumble spheres.

electronicsbyjulie commented 1 year ago

Finding that modeling the dual nature of histidine is going to be vital to accurate predictions.

electronicsbyjulie commented 1 year ago

https://pubs.acs.org/cms/10.1021/acs.jcim.0c00190/asset/images/large/ci0c00190_0002.jpeg

According to the figure, aspartate can increase histidine's pKa if a negatively charged oxygen forms a hydrogen bond with the NH of the imidazole ring. But if a serine forms a hydrogen bond with the plain N of the ring, It has a stabilizing effect and the pKa is only somewhat increased.

From: https://pubs.acs.org/doi/10.1021/acs.jcim.0c00190

So for docking purposes, the entire conjugated system must be evaluated for the influences that affect it, and its pKa can be estimated from those influences. In this case, it looks like a charge of -1 is worth a ΔpKa of about +4.8, while a hydrogen bond donor is worth a ΔpKa of -3.3.