It is generally assumed that the formation of low barrier hydrogen bonds (LBHBs) requires identical proton affinities (ΔPA=0) for the bases linked by the LBHB. This is generally true for LBHBs between identical interface atoms, while values of ΔPA≠0 have been reported for LBHBs connecting chemically different atoms. The inherent asymmetry in heteronuclear LBHBs requires ΔPA≠0 to compensate for the asymmetry in the potential energy surface of the LBHB. A PA mismatch between the bases in joined by a heteronuclear LBHB is therefore the standard case and not an exception from the rule.