K836N

K836 has a minimal contact set — only four neighbors within 5 Angstrom: Trp837 (2.45 Angstrom), Ser835 (2.49 Angstrom), Trp678 (3.37 Angstrom), and Pro838 (4.99 Angstrom). The two tryptophans are the structural feature that makes K836 mechanistically distinctive. Trp837 is the immediate covalent neighbor (the K-W sequence); Trp678 is far away in sequence but only 3.37 Angstrom away in space. Together they form a tryptophan pair that sandwiches the K836 lysine side chain.

The cation-pi interaction is well-documented: positively charged amines (lysine, arginine) and aromatic ring systems (tryptophan, phenylalanine, tyrosine) attract each other through favorable electrostatic interaction with the pi-electron cloud, contributing 2-5 kcal/mol per pair when the geometry is correct. With two tryptophans flanking K836, the lysine almost certainly engages in a cation-pi sandwich — a high-value structural anchor that holds the lumenal domain's local geometry together.

Replacing K836 with asparagine destroys this anchor twice over: the positive charge that drives the cation-pi interaction is gone, and the long aliphatic stem that placed the amine at the correct distance from both tryptophan rings is shortened by three carbons. Asparagine's amide can still form hydrogen bonds (likely with S835 and possibly with one of the tryptophan NH groups), but the cation-pi sandwich is structurally inaccessible.

DynaMut2 reports DeltaDeltaG = -0.64 kcal/mol — destabilising and mild on its face, but the energy function tends to under-read cation-pi losses because these interactions are quantum-mechanical in nature and not fully captured by classical force fields. AlphaMissense at 0.996 reads this position as extremely pathogenic — about as high a score as the model produces. The combination of high AM and modest DeltaDeltaG is the Atlas's clearest signature of a functional-site disruption that energy functions under-report.