Structure Prediction of Binding Sites of MHC Class II Molecules based on the Crystal of HLA-DRB1 and Global Optimization

Abstract

Class II histocompatibility molecules are cell surface molecules that form complexes with self and non-self peptides and present them to T-cells that activate the immune response. A number of class II histocompatibility molecules have been analyzed by crystallography and include the molecules HLA-DR1 [59], HLA-DR3 [22], and I-E ^k [21].

A novel theoretical predictive approach is presented that can determine three dimensional structures of the binding sites of the HLA-II molecules based on the crystallographic data of previously characterized HLA class II molecules. The proposed approach uses the ECEPP/3 detailed potential energy model for describing the energetics of the atomic interactions in the space of substituted residues dihedral angles and employs a rigorous deterministic global optimization algorithm αBB [1, 6, 2, 3, 4] to obtain the global minimum energy conformation of the binding site. The binding sites of the HLA—DR3 and I-E ^k molecules are predicted based on the crystallographic data of HLADR1 [59]. The predicted structures of the binding sites of these molecules exhibit small root mean square differences that range between 1.09–2.03Å (based on all atoms) in comparison to the reported crystallographic data [21, 22]. The energetic driving forces for binding of the predicted structures are also studied using the decomposition-based approach of Androulakis et al. [28] and found to provide very good agreement with the results of the crystallographically obtained binding sites.