Molecular Mechanism and Energy Basis of Conformational Diversity of Antibody SPE7 Revealed by Molecular Dynamics Simulation and Principal Component Analysis.

Jianzhong Chen,Jinan Wang,Weiliang Zhu

doi:10.1038/srep36900

Abstract

More and more researchers are interested in and focused on how a limited repertoire of antibodies can bind and correspondingly protect against an almost limitless diversity of invading antigens. In this work, a series of 200-ns molecular dynamics (MD) simulations followed by principal component (PC) analysis and free energy calculations were performed to probe potential mechanism of conformational diversity of antibody SPE7. The results show that the motion direction of loops H3 and L3 is different relative to each other, implying that a big structural difference exists between these two loops. The calculated energy landscapes suggest that the changes in the backbone angles ψ and φ of H-Y101 and H-Y105 provide significant contributions to the conformational diversity of SPE7. The dihedral angle analyses based on MD trajectories show that the side-chain conformational changes of several key residues H-W33, H-Y105, L-Y34 and L-W93 around binding site of SPE7 play a key role in the conformational diversity of SPE7, which gives a reasonable explanation for potential mechanism of cross-reactivity of single antibody toward multiple antigens.

Highlights

To date, crystal structures of multiple antibodies complexed with antigens and haptens have been determined[15,16,17,18], which provides structural basis for further insight into the relationship of single antibody toward multiple antigens or cross-reactivity of antibodies
Standard Molecular dynamics (MD) simulations were used as the studying tools of current work
To ensure the convergence of MD trajectories, we performed two separate MD simulations on four conformations with different random seeds and some corresponding analyses were listed in Figures S8 and S9

Summary

Introduction

Crystal structures of multiple antibodies complexed with antigens and haptens have been determined[15,16,17,18], which provides structural basis for further insight into the relationship of single antibody toward multiple antigens or cross-reactivity of antibodies. The antibody D1.3 toward lysozyme strongly binds to lysozyme, and efficiently protects against an anti-idiotype antibody[23] These studies show that antibodies can adjust their conformations by rearranging the side chains of several residues to accept different ligands, which means that multiple antigens or haptens can fit into a single antibody-binding site[24,25,26,27,28]. The work from Tawfik et al revealed a large conformational difference in the loops H3 and L3 induced by large sidechain alterations of several key residues, which may imply an underlining important and interesting mechanism of the relationship of single antibody toward multiple antigens. It is significant to reveal molecular mechanism and energy basis of SPE7 conformational diversity at an atomic level for understanding cross-reactivity of antibodies and antibody–drug conjugated anti-disease treatment. We expect that this study can contribute a significant theoretical hint to antibody-drug conjugated anti-disease treatment

Methods

Results

Conclusion