Genetic Polymorphisms Associated with Lithium Response in Bipolar Disorder: An Integrative Review and In Silico Protein–Protein Interaction Analysis

<b>Background/Objectives</b>: Management of bipolar disorder is marked by variability in lithium response, with responders constituting a distinct clinical subgroup. Although pharmacogenetic studies implicate polymorphisms in neuroplasticity-related genes (<i>BDNF</i>) and hypothalamic-pituitary-adrenal (HPA) axis regulators (<i>NR3C1</i>), the underlying biophysical mechanisms remain poorly characterized. This study aims to bridge this structural-mechanistic gap by quantifying the atomic-level effects of key lithium-response polymorphisms on protein-protein interaction stability and conformational dynamics. <b>Methods</b>: Variant sequences for <i>BDNF</i> rs6265 and <i>NR3C1</i> rs56149945 were generated and structurally modeled with SWISS-MODEL. Protein-protein interaction analyses focused on the BDNF-TrkB and NR3C1-FKBP5 systems. Structural alignment and conformational comparisons were performed with ChimeraX and US-align, while interaction energetics were evaluated with PRODIGY and HawkDock. Conformational flexibility was assessed using CABS-flex through RMSF analysis. <b>Results</b>: Structural validation showed acceptable model quality. Binding analyses indicated stronger interactions in the variant complexes. In the BDNF-TrkB complex, binding affinity shifted from -13.8 to -15.1 kcal/mol with an ~8.5-fold lower dissociation constant, while the NR3C1-FKBP5 variant complex shifted from -16.3 to -18.8 kcal/mol with an ~65-fold lower dissociation constant. MM/GBSA calculations supported increased stability, with binding energies changing from -61.98 to -83.91 kcal/mol (BDNF-TrkB) and from -18.88 to -31.25 kcal/mol (NR3C1-FKBP5). Structural superposition showed high conservation of global folds (pruned RMSD 0.779 Å and 0.310 Å; TM-scores 0.753 and 0.967). RMSF profiles were largely overlapping, indicating localized interface adjustments rather than global conformational changes. <b>Conclusions</b>: These findings suggest that lithium-response polymorphisms may modulate protein-protein interaction stability while preserving overall structure, providing a structural framework for exploring genetic influences on lithium treatment response.