Why is Dimeric 3D Domain Swapping in Antibody Light Chains Missing from the Solution? Atomistic Insights Mechanisms

Area of Science:

• Biochemistry
• Structural Biology
• Computational Biophysics

Background:

• Misfolding of antibody light chains is implicated in systemic light chain amyloidosis.
• Antibody light chains may undergo 3D domain swapping (3D-DS) via hydrogen bonding (HB) in the variable region, potentially forming tetramers.
• Experimental detection of 3D-DS dimers has been unsuccessful.

Purpose of the Study:

• To investigate the structural dynamics and stability underlying the absence of experimentally detected 3D-domain swapping (3D-DS) dimers.
• To elucidate the factors contributing to the loss of 3D-DS in antibody light chains.

Main Methods:

• Microscale molecular dynamics simulations of the variable region of antibody light chains (#4V_L) and 3D-DS.
• Analysis of structural dynamics using integrated solvation-based principal component analysis (3D-RISM/PCA) and density-based spatial clustering.
• Evaluation of solvation effects and native hydrogen bonding (HB) interactions.

Main Results:

• Native HB interactions are crucial for maintaining β-sheet structures in both #4V_L and 3D-DS.
• Repulsive interactions with water molecules destabilize HB in the 3D-DS system, inducing breathing motions.
• Inability of the 3D-DS dimer to form a tetramer during breathing motions leads to its collapse.

Conclusions:

• The instability and collapse of the 3D-DS dimer, due to disrupted HB interactions and solvation effects, explain its absence in experimental observations.
• Understanding these dynamics provides insights for designing and developing 3D-DS in other antibodies.