Amphipathicity

A peptide is amphipathic when its hydrophobic and hydrophilic residues sit on opposite faces of the folded structure rather than mixed around it. For a helix this is arithmetic: consecutive residues advance 100 degrees around the axis, so plotting a sequence on a helical wheel shows whether the non-polar residues cluster on one side. The hydrophobic moment quantifies that clustering as a vector sum weighted by angular position, distinguishing a genuinely two-faced helix from one merely hydrophobic overall.

The property defines an entire class of molecules. Antimicrobial peptides such as magainin, LL-37 and the defensins are cationic and amphipathic, and both features are needed: positive charge draws them to the anionic outer surface of bacterial membranes, after which the hydrophobic face inserts into the lipid interior and disrupts the bilayer. Melittin works by the same geometry, which is why bee venom is haemolytic.

Selectivity, not activity, is therefore the design problem. Mammalian outer leaflets are largely zwitterionic and carry cholesterol, so discrimination between a bacterium and a host cell rests mainly on charge, and enlarging the hydrophobic face to raise potency tends to erode it. The useful readout is the ratio between the concentration that lyses red cells and the minimum inhibitory concentration, not either figure alone.

Two misreadings recur. The first quotes a hydrophobic moment computed from sequence as though it were measured, when the calculation assumes a helix a short peptide may never form in water. The second treats membrane disruption in a liposome or broth dilution assay as evidence of therapeutic effect; amphipathic peptides adsorb to vials, aggregate at interfaces and bind serum proteins avidly, and in vitro activity for this class has translated poorly into systemic clinical benefit.