title: Protein/solvent medium effects on Mg(2+)-carboxylate interactions in metalloenzymes.
abstract: We employed umbrella sampling molecular dynamics simulations in explicit water to study the binding of the Mg(2+) cofactor to ribonuclease H (RNase H) from three different organisms. We show that the enzyme can differentiate between different Mg(2+)-binding modes that are nearly equally stable by creating a free-energy barrier between a water-rich mode and a water-depleted mode. Through a comparison with the corresponding free-energy barrier in water, this effect is shown to emanate from the enzymes's three-dimensional architecture and its associated environment. Implications of these protein medium effects in RNase H function and in structure-based drug/molecular design are discussed.
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei 11529, Taiwan, ROC.
authors.forename: C Satheesan
authors.initials: CS
authors.lastname: Babu
authors.forename: Carmay
authors.initials: C
authors.lastname: Lim
mesh_terms: D001665:Binding Sites; D002264:Carboxylic Acids / Q000378:metabolism*; D015195:Drug Design; D004798:Enzymes / Q000737:chemistry* / Q000378:metabolism*; D004926:Escherichia coli / Q000201:enzymology; D015497:HIV-1 / Q000201:enzymology; D009052:Leukemia Virus, Murine / Q000201:enzymology; D008274:Magnesium / Q000378:metabolism*; D008667:Metalloproteins / Q000737:chemistry* / Q000378:metabolism*; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D016914:Ribonuclease H / Q000737:chemistry / Q000378:metabolism; D012997:Solvents / Q000737:chemistry*; D013816:Thermodynamics; D014867:Water / Q000737:chemistry
chemical_list: D002264:Carboxylic Acids; D004798:Enzymes; D008667:Metalloproteins; D012997:Solvents; D014867:Water; D016914:Ribonuclease H; D008274:Magnesium