POSTER NO: 430

In Silico Interactions Between LDLs and LDL-Receptor Binding Modules

Whay K. Lau, Pamela S.T. Ching, Raymond M.W. Chau
Dept. of Anatomy, The University of Hong Kong, 21 Sassoon Rd, Pokfulam, Hong Kong

The mechanisms of familial hypercholesterolaemia and coronary heart disease as well as the structures of LDL and its receptor have been studied intensively. We have recently focused on the structural interaction between the LDL and LDLR, especially on the interacting amino acids between them and the 3D molecular surface of the interacted complex. We are interested in interactions between ligand-binding module (LB) 5 and Apo E3, LB5 and Apo B-100 as well as LB6 and Apo B-100, because LB5 [1AJJ] is known to preferentially bind Apo E3 [1LPE] but is also capable of binding Apo B-100 whereas LB6 [1D2J] contributes to the binding of Apo B-100 [we constructed it in PDB file by homology modeling]. Using SwissPDB Viewer and GRAMM docking programme to produce 3D image and docking energy of 3000 docks for each of the above complexes as well as statistical analysis of the energy-atomic distance-group distribution of these docks, we have investigated the molecular surface and atomic interactions at the sites of interaction of each complex with relatively accurate and reliable results. The results for LB5 and APO E3 complex revealed that the more hydrophobic and basic molecular surface of APO E3 changed significantly to highly acidic in the docked complex, which exhibited the most stable docking energy of -349; and that the interacting amino acids on LB5 are P4, S6, E9, E16, C17, H19, W22, D25, P28 and D29 whereas on APO E3, they are R92, K95, E96, R103, R150 and R158. The Ca++ co-ordinating center on LB5 involves W22, D25, G27, D29, D35 and E36. It is clear that the acidic amino acids on LB5 is specifically interacting with the basic amino acids on APO E3 and their specific atomic interactions and bond lengths were also analyzed. The results for LB5 and APO B-100 complex revealed that the major acidic molecular surface of APO B-100 did not change much in the docked complex except in four spotted areas where two hydrophobic and basic spots changed into acidic surface and the other two hydrophobic and basic spots changed into pure hydrophobic spots. This docked complex which is consistent with the above LB5 and APO E3 complex, exhibited a docking energy of -294; and that the interacting amino acids on LB5 are K33, E37 and N38 whereas on APO B-100, they are K1207, K1210, E1211 and Y1280. Clearly, the interaction of this complex is less stable and readily compared to the previous one, but it is still based on complementary electrostatic interactions between amino acids on LB5 and APO B-100. The results for LB6 and APO B-100 complex revealed that the major acidic molecular surface of APO B-100 did not change much in the docked complex except in two spotted areas and two surface areas. The two spotted areas which are hydrophobic and basic, changed into one pure hydrophobic spot and one acidic surface. Also from the acidic surface, there arose additional three hydrophobic and basic spots. The best-fit docked complex of LB6 and APO B-100 exhibited a docking energy of -327, which shows APO B-100 preferentially binds LB6 compared to LB5. The results also showed that the interacting amino acids on LB6 similar to those in the Ca++ co-ordinating center are R232, D235, R236, E237, Y238 and D239 whereas on APO B-100, they are I1206, K1210, K1213 and L1217. The interacting atoms and bond lengths of their amino acids between LB6 and APO B-100 were also analyzed. Therefore, the present results support LB5 and LB6 interacting with APO E3 and APO B-100, respectively, via their Ca++ co-ordinating centers.