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

Misfolding\nof antibody light chains can lead to systemic light\nchain amyloidosis, which is associated with misfolding and aggregation.\nThe antibody light chain may engage in 3D domain swapping within the\nvariable region (#4V<sub>L</sub>) through hydrogen bonding (HB) interactions,\npotentially forming the tetramer, as revealed in solution and crystal\nstructures. However, the 3D-domain swapping (3D-DS) dimers could not\nbe detected experimentally. This study investigates the absence of\n3D-DS using computational approaches, focusing on structural dynamics,\nsolvation effects, and stability relevant to the loss of 3D-DS. Microscale\nmolecular dynamics simulations of #4V<sub>L</sub> and 3D-DS confirm\nthat native HB interactions are essential to maintain β-sheet\nstructures in both #4V<sub>L</sub> and 3D-DS. A flickering native\nHB interaction in the 3D-DS system, caused by repulsive interaction\nwith water molecules in the hydrophobic region, leads to intramolecular\nbreathing motions and oligomerization in another 3D-DS. Structural\ndynamics of the 3D-DS dimer in long-run simulations were analyzed\nusing the newly developed integrated solvation-based principal component\nanalysis (3D-RISM/PCA) and density-based spatial clustering of applications\nwith noise, confirm that if the 3D-DS cannot form the tetramer within\nthe breathing motion process, the 3D-DS will collapse. This finding\nprovides insights into why the 3D-DS dimer is missing from the solution\nand can be used to design and develop 3D-DS in other antibodies.