Antibody affinity maturation is one of the fundamental processes of immune defense against invading pathogens. From the biological point of view, the clonal selection hypothesis represents the most accepted mechanism to explain how mutations increasing the affinity for target antigens are introduced and selected in antibody molecules. However, understanding at the molecular level how protein modifications, such as point mutation, can modify and modulate the affinity of an antibody for its antigen is still a major open issue in molecular biology. In this paper, we address various aspects of this problem by analyzing and comparing atomistic simulations of 17 variants of the bevacizumab antibody, all directed against the common target protein VEGF-A. In particular, we examine MD-based descriptors of the internal energetics and dynamics of mutated antibodies and their possible correlations with experimentally determined affinities for the antigens. Our results show that affinity improvement is correlated with a variation of the internal stabilization energy of the antibody molecule when bound to the antigen, compensated by the variation in the interaction energy between the antigen and the antibody, paralleled by an overall modulation of internal coordination within the antibody molecular structure. A possible model of the mechanism of rigidification and of the main residues involved is proposed. Overall, our results can help in understanding the molecular determinants of antigen recognition and have implications in the rational design of new antibodies with optimized affinities.

Corrada, D., Colombo, G. (2013). Energetic and dynamic aspects of the affinity maturation process: characterizing improved variants from the bevacizumab antibody with molecular simulations. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 53(11), 2937-2950 [10.1021/ci400416e].

Energetic and dynamic aspects of the affinity maturation process: characterizing improved variants from the bevacizumab antibody with molecular simulations

CORRADA, DARIO;
2013

Abstract

Antibody affinity maturation is one of the fundamental processes of immune defense against invading pathogens. From the biological point of view, the clonal selection hypothesis represents the most accepted mechanism to explain how mutations increasing the affinity for target antigens are introduced and selected in antibody molecules. However, understanding at the molecular level how protein modifications, such as point mutation, can modify and modulate the affinity of an antibody for its antigen is still a major open issue in molecular biology. In this paper, we address various aspects of this problem by analyzing and comparing atomistic simulations of 17 variants of the bevacizumab antibody, all directed against the common target protein VEGF-A. In particular, we examine MD-based descriptors of the internal energetics and dynamics of mutated antibodies and their possible correlations with experimentally determined affinities for the antigens. Our results show that affinity improvement is correlated with a variation of the internal stabilization energy of the antibody molecule when bound to the antigen, compensated by the variation in the interaction energy between the antigen and the antibody, paralleled by an overall modulation of internal coordination within the antibody molecular structure. A possible model of the mechanism of rigidification and of the main residues involved is proposed. Overall, our results can help in understanding the molecular determinants of antigen recognition and have implications in the rational design of new antibodies with optimized affinities.
Articolo in rivista - Articolo scientifico
antibodies; bevacizumab; affinity maturation; molecular dynamics
English
2937
2950
14
Corrada, D., Colombo, G. (2013). Energetic and dynamic aspects of the affinity maturation process: characterizing improved variants from the bevacizumab antibody with molecular simulations. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 53(11), 2937-2950 [10.1021/ci400416e].
Corrada, D; Colombo, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/48630
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