Reactions of methyl (S)‐2‐[(2‐hydroxybenzylidene)amino]‐3‐(1H‐imidazol‐4‐yl)propanoate (S‐H2LMe) and various transition‐metal(II) salts (MX2: M = Mn, Fe, Co, and Ni; X = ClO4, Cl, OAc, etc.) are examined. During the reactions with MnII and CoII salts, the MII ion is oxidized by air to form a cationic complex with two mono‐deprotonated ligands, [MIII(S‐HLMe)2]X [M, X = Mn, ClO4 (S‐1ClO4); Co, ClO4 (S‐3ClO4); and Co, Cl (S‐3Cl)], where (S‐HLMe)– is coordinated to a MIII center in a tridentate κ3O,N,N′ mode with a mer configuration. In contrast, the NiII ion is not oxidized; only one of the ligands is deprotonated to form a similar monocationic complex, [NiII(S‐HLMe)(S‐H2LMe)]PF6 (S‐6PF6), which forms a dimer structure by double hydrogen bonds between the coordinating phenoxide and phenol groups in the crystal. Interestingly, the above complexes show slow racemization of the ligand, as confirmed by circular dichroism spectroscopy. Racemic NiII complexes of [Ni(HLMe)(H2LMe)](PF6 or Cl) (rac‐6PF6 or rac‐6Cl) are isolated and their crystal structures are confirmed by X‐ray diffraction analysis. In the case where Co(OAc)2 is used as the metal(II) salt, a new ligand dimerization reaction takes place to afford a complex of [Co(H2LLMe)]Cl (7Cl, H4LLMe = methyl (E)‐3‐{[3‐(1H‐imidazol‐4‐yl)‐1‐methoxy‐1‐oxopropano‐2‐yl]amino}‐2‐[(1H‐imidazol‐4‐yl)methyl]‐2‐[(2‐hydroxybenzylidene)amino]‐3‐(2‐hydroxyphenyl)propanoate).

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We employed a multivalent peptide-library screening technique to identify a peptide motif that binds to phosphatidic acid (PA), but not to other phospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylserine (PS). A tetravalent peptide with the sequence motif of MARWHRHHH, designated as PAB-TP (phosphatidic acid-binding tetravalent peptide), was shown to bind as low as 1 mol% of PA in the bilayer membrane composed of PC and cholesterol. Kinetic analysis of the interaction between PAB-TP and the membranes containing 10 mol% of PA showed that PAB-TP associated with PA with a low dissociation constant of KD = 38 ± 5 nM. Coexistence of cholesterol or PE with PA in the membrane enhanced the PAB-TP binding to PA by increasing the ionization of the phosphomonoester head group as well as by changing the microenvironment of PA molecules in the membrane. Amino acid replacement analysis demonstrated that the tryptophan residue at position 4 of PAB-TP was involved in the interaction with PA. Furthermore, a series of amino acid substitutions at positions 5 to 9 of PAB-TP revealed the involvement of consecutive histidine and arginine residues in recognition of the phosphomonoester head group of PA. Our results demonstrate that the recognition of PA by PAB-TP is achieved by a combination of hydrophobic, electrostatic and hydrogen-bond interactions, and that the tetravalent structure of PAB-TP contributes to the high affinity binding to PA in the membrane. The novel PA-binding tetravalent peptide PAB-TP will provide insight into the molecular mechanism underlying the recognition of PA by PA-binding proteins that are involved in various cellular events.

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