2as6
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cytochrome c peroxidase in complex with cyclopentylamine
OverviewOverview
A model binding site was used to investigate charge-charge interactions in, molecular docking. This simple site, a small (180A(3)) engineered cavity, in cyctochrome c peroxidase (CCP), is negatively charged and completely, buried from solvent, allowing us to explore the balance between, electrostatic energy and ligand desolvation energy in a system where many, of the common approximations in docking do not apply. A database with, about 5300 molecules was docked into this cavity. Retrospective testing, with known ligands and decoys showed that overall the balance between, electrostatic interaction and desolvation energy was captured. More, interesting were prospective docking scre"ens that looked for novel, ligands, especially those that might reveal problems with the docking and, energy methods. Based on screens of the 5300 compound database, both, high-scoring and low-scoring molecules were acquired and tested for, binding. Out of 16 new, high-scoring compounds tested, 15 were observed to, bind. All of these were small heterocyclic cations. Binding constants were, measured for a few of these, they ranged between 20microM and 60microM., Crystal structures were determined for ten of these ligands in complex, with the protein. The observed ligand geometry corresponded closely to, that predicted by docking. Several low-scoring alkyl amino cations were, also tested and found to bind. The low docking score of these molecules, owed to the relatively high charge density of the charged amino group and, the corresponding high desolvation penalty. When the complex structures of, those ligands were determined, a bound water molecule was observed, interacting with the amino group and a backbone carbonyl group of the, cavity. This water molecule mitigates the desolvation penalty and improves, the interaction energy relative to that of the "naked" site used in the, docking screen. Finally, six low-scoring neutral molecules were also, tested, with a view to looking for false negative predictions. Whereas, most of these did not bind, two did (phenol and 3-fluorocatechol). Crystal, structures for these two ligands in complex with the cavity site suggest, reasons for their binding. That these neutral molecules do, in fact bind, contradicts previous results in this site and, along with the alkyl, amines, provides instructive false negatives that help identify weaknesses, in our scoring functions. Several improvements of these are considered.
About this StructureAbout this Structure
2AS6 is a Single protein structure of sequence from Saccharomyces cerevisiae with HEM and 1CB as ligands. Active as Cytochrome-c peroxidase, with EC number 1.11.1.5 Full crystallographic information is available from OCA.
ReferenceReference
Probing molecular docking in a charged model binding site., Brenk R, Vetter SW, Boyce SE, Goodin DB, Shoichet BK, J Mol Biol. 2006 Apr 14;357(5):1449-70. Epub 2006 Feb 2. PMID:16490206
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