Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
A Database/Webserver for Size-Independent Quantification of Ligand Binding Site Burial Depth in Receptor Proteins: Implications on Protein Dynamics
We have developed a database/webserver that implements the two complementary methods to quantify the degree of burial of ligand and/or ligand binding site (LBS) in a protein-ligand complex, namely, the ‘secant plane’ (SP) and the ‘tangent sphere’ (TS) methods, which we reported earlier (1). To recapitulate the SP and TS methods: the protein molecular centroid (global centroid, GC), and the LBS centroid (local centroid, LC) are first determined. The SP is defined as the plane passing through the LBS centroid (LC) and normal to the line passing through the LC and the protein molecular centroid (GC). The “exterior side” of the SP is the side opposite GC. The TS is defined as the sphere with center at GC and tangent to the SP at LC. The percentage of protein atoms (a.) inside the TS (a.k.a. ‘TS index’) and (b.) on the exterior side of the SP (a.k.a. ‘SP index’), are two complementary measures of ligand or LBS burial depth since the latter is directly proportional to (b.) and inversely proportional to (a.). We tested the SP and TS methods using a test set of 67 well characterized protein-ligand structures (2), as well as the theoretical case of an artificial protein in the form of a cubic lattice grid of points in the overall shape of a sphere and in which LBS of any depth can be specified. Results from both the SP and TS methods agree very well with reported data (2), and results from the theoretical case further confirm that both methods are suitable measures of ligand or LBS burial. There are two modes by which one can utilize our database/ webserver. In the first mode we term the ‘ligand mode’, the user inputs the PDB structure coordinates of the protein as well as those of its ligand (one ligand at a time if more than one). The second mode - the ‘LBS mode’- is the same as the first except that the ligand coordinates are assumed to be unavailable, hence the user inputs what s/he believes to be the LBS amino acid residues’ coordinates. In both cases, the webserver outputs the SP and TS indices. LBS burial depth is an important parameter as it is usually directly related to the amount of conformational change a protein undergoes upon ligand binding, and ability to quantify it could allow meaningful comparison of protein flexibility and dynamics. The URL of our database/ webserver will be http:// tortellini. bioinformatics. rit. edu/ sxc6274/ thesis1.php and will be made freely available to the community very soon.
Biological Sciences Dept.