BACKGROUND: Although the etiology of chronic lymphocytic leukemia (CLL), the most common type of adult leukemia, is still unclear, strong evidence implicates antigen involvement in disease ontogeny and evolution. Primary and 3D structure analysis has been utilised in order to discover indications of antigenic pressure. The latter has been mostly based on the 3D models of the clonotypic B cell receptor immunoglobulin (BcR IG) amino acid sequences. Therefore, their accuracy is directly dependent on the quality of the model construction algorithms and the specific methods used to compare the ensuing models. Thus far, reliable and robust methods that can group the IG 3D models based on their structural characteristics are missing. RESULTS: Here we propose a novel method for clustering a set of proteins based on their 3D structure focusing on 3D structures of BcR IG from a large series of patients with CLL. The method combines techniques from the areas of bioinformatics, 3D object recognition and machine learning. The clustering procedure is based on the extraction of 3D descriptors, encoding various properties of the local and global geometrical structure of the proteins. The descriptors are extracted from aligned pairs of proteins. A combination of individual 3D descriptors is also used as an additional method. The comparison of the automatically generated clusters to manual annotation by experts shows an increased accuracy when using the 3D descriptors compared to plain bioinformatics-based comparison. The accuracy is increased even more when using the combination of 3D descriptors. CONCLUSIONS: The experimental results verify that the use of 3D descriptors commonly used for 3D object recognition can be effectively applied to distinguishing structural differences of proteins. The proposed approach can be applied to provide hints for the existence of structural groups in a large set of unannotated BcR IG protein files in both CLL and, by logical extension, other contexts where it is relevant to characterize BcR IG structural similarity. The method does not present any limitations in application and can be extended to other types of proteins.

Carlsberg Research Laboratory Copenhagen Denmark

Center for Biological Sequence Analysis Technical University of Denmark Copenhagen Denmark

Department of Immunology Technical University of Denmark Genetics and Pathology Science for Life Laboratory Uppsala University Uppsala Sweden

Department of Informatics Ionian University Corfu Greece

Hematology Department and HCT Unit G Papanikolaou Hospital Thessaloniki Greece

Information Technologies Institute Centre for Research and Technology Hellas 6th km Harilaou Thermi Road Thessaloniki Greece

Institute of Applied Biosciences Centre for Research and Technology Hellas 6th km Harilaou Thermi Road Thessaloniki Greece

IRCCS San Raffaele Scientific Institute and Università VitaSalute San Raffaele Division of Experimental Oncology Milan Italy

Karches Center for Chronic Lymphocytic Leukemia Research The Feinstein Institute for Medical Research Manhasset NY USA

Masaryk University Central European Institute of Technology Brno Czech Republic

Nikea General Hospital Hematology Department Piraeus Greece

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Higher-order connections between stereotyped subsets: implications for improved patient classification in CLL