Hydrophobic interaction with an aromatic carbon bound to a nitrogen

[papillot]

The interaction between the Leu141 and the aromatic carbon in the following network plot quizzes me:

The aromatic carbon is attached to a nitrogen which would give it a positive partial charge.

Looking at the corresponding SMARTS for this interaction:

[c,s,Br,I,S&H0&v2,$([D3,D4;#6])&!$([#6]~[#7,#8,#9])&!$([#6X4H0]);+0]

The lowercase c at the start of this pattern, with the , (OR) combinator means that any aromatic carbon satisfies the selector.
The pattern $([D3,D4;#6])&!$([#6]~[#7,#8,#9])&!$([#6X4H0]) takes into consideration any carbon (aromatic or aliphatic #6) and amongst other things, discards the ones that are bound to a nitrogen via any kind of bond (the [#6]~[#7,#8,#9] part)
This second pattern can not be evaluated for aromatic carbons because of the truthiness of c at the beginning of the SMARTS string.

Is there a specific consideration for always allowing aromatic carbons to make hydrophobic interactions?

[cbouy]

Hi,

Is there a specific consideration for always allowing aromatic carbons to make hydrophobic interactions?

IIRC this part of the SMARTS comes from the RDKit pharmacophore definitions, and I think Pharmit (which I also used as an inspiration for some of the other SMARTS) also accepts any aromatic atom as hydrophobic.

Plus to take these sorts of effects into account a bit more accurately, we'd have to consider how the different substituents may activate or deactivate the ring so that would be quite complicated to generalise and express in a SMARTS pattern.

If need be you can easily modify the SMARTS (and any other interaction parameter) being used to fit your case:

fp = plf.Fingerprint(
    parameters={
        "Hydrophobic": {
            "hydrophobic": "<custom SMARTS here>"
        }
    }
)

Please close the issue if this answers your question

[papillot]

Thanks for the detailed answer!