Move from predicting pKa to choosing a placement
PROPKA already estimates pKa values in proteins and protein–ligand complexes. BioTwin’s design operation asks where a candidate cation could be placed, then evaluates electrostatic effects, clashes and solvent exposure. The resulting geometry can become a constraint for a linker or recognition element.
More thiolate does not guarantee the desired rate
Changing acidity also changes nucleophilic behavior. The model includes Brønsted compensation so a predicted pKa shift is interpreted through its effect on reaction kinetics. Combined with recognition, tether geometry and exposure, this gives a specific molecular hypothesis to compare with simply increasing intrinsic warhead reactivity.
The matched compound is the meaningful test
The design lever has been used in computational Lp(a) work. Actual local pKa shifts and the benefit of a synthesized compound remain unmeasured. A matched pair with and without the charged feature should distinguish changes in binding, local reactivity and off-target capture. Desolvation and molecular realization can overturn a favorable electrostatic estimate.