Halogen bonds (X-bonds) are shown to be geometrically perpendicular to and energetically independent of hydrogen bonds (H-bonds) that share a common carbonyl oxygen acceptor. This orthogonal relationship is accommodated by the in-plane and out-of-plane electronegative potentials of the oxygen, which are differentially populated by H- and X-bonds. Furthermore, the local conformation of a peptide helps to define the geometry of the H-bond and thus the oxygen surface that is accessible for X-bonding. These electrostatic and steric forces conspire to impose a strong preference for the orthogonal geometry of X- and H-bonds. Thus, the optimum geometry of an X-bond can be predicted from the pattern of H-bonds in a folded protein, enabling X-bonds to be introduced to improve ligand affinities without disrupting these structurally important interactions. This concept of orthogonal molecular interactions can be exploited for the rational design of halogenated ligands as inhibitors and drugs, and in biomolecular engineering.

when expressed from the weak authentic RNQ1 promoter. The majority of these mutated residues are mapped to the surface, and on one side, of contiguous a-helices of the nonprion domain of Rnq1, suggesting its involvement in interactions with a prion or a factor necessary for prion development.

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