Abstract for InCoB, New Delhi, 2006
Category: Drug Design
Presenting author: Carmay Lim, National Tsing Hua U, Taipei

 Factors Governing the Maximum Number of Metal-bound Carboxylates in Metalloproteins

Todor Dudev, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Phone: 2789-9043; E-mail: todor@ibms.sinica.edu.tw

Carmay Lim, Institute of Biomedical Sciences, Academia Sinica, Taipei 115, Taiwan, Phone: 2652-3031; E-mail: carmay@gate.sinica.edu.tw

 The number of negatively charged metal-bound Asp/Glu residues determines the net charge of the carboxylate-rich metal-binding site, which has been found to play a role in enhancing the affinity and/or selectivity of a protein cavity for a given metal co-factor. Therefore, it is of interest to know the maximum number of carboxylates that could bind to a given metal (Mq+) of charge q, and the key factors determining this upper limit in protein cavities, which are usually relatively buried. Using density functional theory combined with the continuum dielectric method to compute the H2O®CH3COO- exchange free energies, the maximum number of carboxylates bound to Mq+ in a relatively buried metal-binding site is found to depend on (i) the metal charge, q, (ii) the carboxylate-binding mode, and (iii) the first-shell carboxylate- second-shell ligand interactions. The maximum number of carboxylates bound to Mq+ in a fully/partially solvent inaccessible protein cavity would not likely exceed q+2 if (a) the metal-bound Asp/Glu side chains are hydrogen bonded to a Lys/Arg side chain or several peptide backbone amides/Asn/Gln side chains in the metal’s second coordination shell, or (b) at least one acidic residue binds bidentately, as opposed to monodentately, to the metal cofactor. This number is reduced to q+1 in the absence of stabilizing interactions from outer-shell ligand(s), and if all the carboxylates are bound monodentately to the metal co-factor in a buried cavity. The computational results are consistent with findings from a PDB survey of uni, di, and trivalent metal-binding sites containing Asp/Glu residues

 References

Todor Dudev and Carmay Lim, J. Am. Chem. Soc. (2006) 128: 1553-1561.

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