HLA-Modeler: Automated Homology Modeling of Human Leukocyte Antigens

The three-dimensional (3D) structures of human leukocyte antigen (HLA) molecules are indispensable for the studies on the functions at molecular level. We have developed a homology modeling system named HLA-modeler specialized in the HLA molecules. Segment matching algorithm is employed for modeling and the optimization of the model is carried out by use of the PFROSST force field considering the implicit solvent model. In order to efficiently construct the homology models, HLA-modeler uses a local database of the 3D structures of HLA molecules. The structure of the antigenic peptide-binding site is important for the function and the 3D structure is highly conserved between various alleles. HLA-modeler optimizes the use of this structural motif. The leave-one-out cross-validation using the crystal structures of class I and class II HLA molecules has demonstrated that the rmsds of nonhydrogen atoms of the sites between homology models and crystal structures are less than 1.0？？ in most cases. The results have indicated that the 3D structures of the antigenic peptide-binding sites can be reproduced by HLA-modeler at the level almost corresponding to the crystal structures. 1. Introduction The cause of various diseases involves the human leukocyte antigen (HLA) system which is the human version of the major histocompatibility complex. The HLA genes involved in the immune response fall into two classes, I and II, which are structurally and functionally different. Typical diseases associated with HLA molecules are autoimmune diseases [1] and infectious diseases [2]. The association between specific HLA alleles and adverse drug reactions which frequently cause significant morbidity and mortality for patients is also widely known [3]. A reliable three-dimensional (3D) structure of the particular HLA allele responsible for the specific event is essential to understand the underlying molecular mechanism in order to develop effective therapeutic agents or/and countermeasures. Since the pioneering work by Wiley et al. [4], various crystal structures of the HLA molecules have been disclosed so far. The crystal structures have shown that the peptide-binding groove of an HLA molecule consists of two parts, a floor and two walls. Although this canonical topology is highly conserved among different alleles, certain structural differences exist depending on the alleles. Therefore, the 3D structure of a particular HLA molecule is required for HLA studies. The HLA genes are the most polymorphic in the human genome and there are a large number of allelic variations. In the