Probing conformational dynamics of antibodies with geometric simulations

TL;DR

This paper demonstrates the use of constrained geometric simulations, specifically FRODAN, to efficiently analyze antibody conformational dynamics, revealing large amplitude motions relevant to antibody function.

Contribution

It introduces FRODAN as a low-cost, all-atom simulation method for studying protein flexibility, especially for large proteins and long timescales.

Findings

Antibodies explore a large conformational space.

FRODAN accurately predicts domain motions.

Antibody CDR loops exhibit significant flexibility.

Abstract

This chapter describes the application of constrained geometric simulations for prediction of antibody structural dynamics. We utilize constrained geometric simulations method FRODAN, which is a low computational complexity alternative to Molecular Dynamics (MD) simulations that can rapidly explore flexible motions in protein structures. FRODAN is highly suited for conformational dynamics analysis of large proteins, complexes, intrinsically disordered proteins and dynamics that occurs on longer biologically relevant time scales which are normally inaccessible to classical MD simulations. This approach predicts protein dynamics at an all-atom scale while retaining realistic covalent bonding, maintaining dihedral angles in energetically good conformations while avoiding steric clashes in addition to performing other geometric and stereochemical criteria checks. In this chapter, we apply FRODAN to showcase its applicability for probing functionally relevant dynamics of IgG2a, including large amplitude domain-domain motions and motions of complementarity determining region (CDR) loops. As was suggested in previous experimental studies, our simulations show that antibodies can explore a large range of conformational space.