Studying how different terminal groups change the motion of H2NSO2C6H4CONH(EG)3R when bound to the active site of human carbonic anhydrase II.
Molecular dynamics simulations have been used to explore the motions of series of ligands containing coupled benzenesulfonamide and oligoethylene glycol moieties (H2NSO2C6H4CONH(CH2-CH2OCH2CH2OCH2CH2)R+; R+ = NH3+, NHCOCH2NH3+, NHCOCH(CH2Ph)NH3+) bound at the active site of human carbonic anhydrase II (HCAII; E.C. 4.2.1.1). These complexes have been examined previously by X-ray crystallography; the locations of the terminal groups of these ligands were not defined in the crystal structures. These stimulations, carried out in the presence of water, provide dynamic information about the motion of the bound ligand that supplements the quasistatic information from crystallography. Our results suggested that the Gly and Phe groups of these ligands interacted weakly with the protein adjacent to the active site. Quantitative estimates of energies of binding did not correlate usefully with observed free energies of binding, but in the absence of information about entropies, it is not possible to tell if the lack of correlation between calculated energies and observed free energies represents inaccuracies in the energies, or a compensation between enthalpies and entropies. When the terminal Phe group was placed near a previously identified hydrophobic patch in the active site (Phe20 and Pro202) the average conformation of the ligand inferred from this simulation was inconsistent with that from the crystal structure; this result illustrates the problems of misleading local minima in these types of simulations.
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Department of Chemistry, and Chemical Biology, Harvard University, 12 Oxford Street, Cambridge, Massachusetts 02138, USA.
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Whitesides
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D001665:Binding Sites; D024402:Carbonic Anhydrase II / Q000737:chemistry / Q000378:metabolism*; D002257:Carbonic Anhydrase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D019855:Ethylene Glycol / Q000737:chemistry / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D010649:Phenylalanine / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology*; D013816:Thermodynamics
D002257:Carbonic Anhydrase Inhibitors; D008024:Ligands; D013449:Sulfonamides; D010649:Phenylalanine; D011392:Proline; D024402:Carbonic Anhydrase II; D019855:Ethylene Glycol; D005998:Glycine