POSTER NO: 432

Computational characterization of receptor binding for monocyte chemoattractant protein 1 (MCP-1)

²F.K. Li, ¹Raymond M.W. Chau
¹Dept. of Anatomy, The University of Hong Kong, 21 Sassoon Rd, Pokfulam, Hong Kong, ²Division of Nephrology, Dept. of Medicine, Queen Mary Hospital, The University of Hong Kong, Rm 302 New Clinical Building, 102 Pokfulam Rd, Hong Kong

Monocyte chemotactic protein 1 (MCP-1) is an important monocyte chemoattractant relevant to the recruitment of mononuclear cells to the site of inflammation. There is, however, significant controversy with regard to the molecular interaction of MCP-1 to its putative receptor, CCR2-beta. The binding of MCP-1 to CCR2-beta has been studied and is most likely resulting from monomeric interaction between the chemokine and its receptor. To further study the atomic interaction of MCP-1 receptor binding, we docked MCP-1 [1DOL, 71 amino acid peptide] with its putative receptor CCR2-beta [1KAD] in SwissPDB Viewer and GRAMM docking programme. The possible sites of interaction and their significance were examined. The results of molecular surface revealed that before docking, over 50% surface of MCP-1 and 75% surface of CCR2-beta are basic surface and the rest of their surface are shared between acidic and hydrophobic surface; and that after docking, over 85% of the total surface of the docked complex became basic surface. The acidic region of MCP-1 having amino acids E40, D63, D66 and D69 reacted complementary to the basic region of CCR2-beta composing amino acids R8, H33, K34, H100, K114, K180, R196 and R206. Both of these acidic and basic regions of MCP-1 and CCR2-beta are also structurally complementary to each other. As a result, the molecular surface of both reacting regions changed from acidic and hydrophobic surface to all basic surfaces. There were seven potential sites of atomic interaction between MCP-1 and CCR2-beta. They reside in the following positions: [1] M1-S<-->O=C-I176 (the sulfur atom in the first amino acid methionine of MCP-1 interacts with the carbonyl oxygen in the 176th amino acid isoleucine of CCR2-beta) with bond length of 3.33A; [2] Y29-C=O<-->Ne1-W198 of 4.49A; [3] R31-NH1<-->O=C-N12 of 3.21A; [4] Q62-Ne2<-->O=C-I10 of 3.98A; [5] D69-Od1<-->Nd2-N200 of 3.06A; [6] K70-C=O<-->Ne2-Q269 of 4.41A and [7] Q71-Ne2<-->O=C-E270 of 4.08A. There are intra-molecular interactions within the MCP-1 at [8] D63-Od2<-->Nz-K59 of 4.1A and also within the CCR2-beta at [9] N2-C=O<-->Nz-K180 of 2.76A. These data, when complemented with experiments studying mutagenesis, are of fundamental importance for the rational design of specific structure- and mechanism-based inhibitors.