Abstract
IgG subclass-specific differences in biological function and in vitro stability are
often referred to variations in the conformational flexibility, while this flexibility
has rarely been characterized. Here, small-angle X-ray scattering data from
IgG1, IgG2 and IgG4 antibodies, which were designed with identical variable
regions, were thoroughly analysed by the ensemble optimization method. The
extended analysis of the optimized ensembles through shape clustering reveals
distinct subclass-specific conformational preferences, which provide new insights
for understanding the variations in physical/chemical stability and biological
function of therapeutic antibodies. Importantly, the way that specific differences
in the linker region correlate with the solution structure of intact antibodies is
revealed, thereby visualizing future potential for the rational design of
antibodies with designated physicochemical properties and tailored effector
functions. In addition, this advanced computational approach is applicable to
other flexible multi-domain systems and extends the potential for investigating
flexibility in solutions of macromolecules by small-angle X-ray scattering.
often referred to variations in the conformational flexibility, while this flexibility
has rarely been characterized. Here, small-angle X-ray scattering data from
IgG1, IgG2 and IgG4 antibodies, which were designed with identical variable
regions, were thoroughly analysed by the ensemble optimization method. The
extended analysis of the optimized ensembles through shape clustering reveals
distinct subclass-specific conformational preferences, which provide new insights
for understanding the variations in physical/chemical stability and biological
function of therapeutic antibodies. Importantly, the way that specific differences
in the linker region correlate with the solution structure of intact antibodies is
revealed, thereby visualizing future potential for the rational design of
antibodies with designated physicochemical properties and tailored effector
functions. In addition, this advanced computational approach is applicable to
other flexible multi-domain systems and extends the potential for investigating
flexibility in solutions of macromolecules by small-angle X-ray scattering.
| Original language | English |
|---|---|
| Journal | IUCrJ |
| Volume | 2 |
| Issue number | 1 |
| Pages (from-to) | 9-18 |
| Number of pages | 10 |
| ISSN | 2052-2525 |
| DOIs | |
| Publication status | Published - 1 Jan 2015 |