Hydrophobic and amphipathic alpha-helices act as independent functional units in immunogenic or fusogenic polypeptides and constitute important structural building blocks in larger membrane proteins. In order to quantitatively assess the interactions that determine the alignment of membrane-associated alpha-helices, hydrophobic model peptides containing histidine residues at selected sites were prepared by solid-phase peptide synthesis. CD and solution NMR spectroscopy show that these peptides assume alpha-helical secondary structures in micellar environments. The chemical shift alterations of the histidine side-chain protons during pH titration experiments indicate that the pK values of the histidine imidazole protons range from 4.9 to 6.6 in the presence of dodecylphosphocholine micelles. 15N solid-state NMR spectroscopy was used to determine the membrane alignment of these peptide alpha-helices in uniaxially oriented phospholipid bilayers. The observed pH-dependent change of orientation of one of these model peptides is quantitatively described by a dynamic equilibrium governed by both electrostatic and hydrophobic protein-lipid interactions. The thermodynamic equations presented provide a means for the prediction of membrane protein structure and topology, as well as the future design of peptide channels and pharmaceuticals.