A thermodynamic analysis discriminating loop backbone conformations

Abstract

Publisher Summary The X-ray crystal structures of antibodies revealed that complementarity determining regions (CDRs) are loop connecting β-strands located at the extremity of a well-conserved β-barrel fold known as the framework (FR). Although X-ray diffraction studies provide accurate description of molecules at an atomic level, it is a time consuming task to undertake. Because of the very high structural similarity of the framework conformation, attempts have been made to model new antibody conformations using homology modeling techniques. Moreover, these modeling experiments provide a basis for integrating and testing the understanding of antibody structure. The major challenge in this approach is to adequately search conformational space for the six hypervariable loops or CDRs, three for the light chain and three for the heavy chain to obtain accurate models. This chapter discusses results concerning the development of a complete physical treatment that allows the screening of loop conformations to identify the most suitable options for a particular antibody model. A formalism has been established that allows the computation of the conformational free energies of loops by combining a molecular mechanic treatment of a loop with a continuum treatment of the solvent. A model study has been stimulated by removing the three light chain CDRs from a recently solved crystal structure of an antibody in a bound conformation—namely, Fab R45-45-11 (R45), then replacing loops from the database and calculating the conformational free energies for each conformation. The results reveal that loops in the database having the lowest conformational energy are the loops with the smallest root-mean-square deviation (RMSD) compared to CDRs of R45. The thermodynamic analysis is expected to be generally useful for antibody modeling.