Structural Analysis of NR1H3 Variants (R415Q, P199H, S440C) Reveals Residue-Specific Grounding for RXR-Interface Disruption in Familial Multiple Sclerosis (MS)

Abstract

Familial Multiple Sclerosis (MS) has been proposed to exhibit a biological association with the R415Q mutation in the Liver X Receptor Alpha (LXRA) protein, in which the subsequent localized discrepancies on the protein's structure are alleged to disrupt heterodimerization (Salles, in review). Unlike R415Q, other NR1H3 variants, such as P199H and S440C, have not yet been evaluated for such associations, though analogous propositions are plausible due to the variants' structural similarities. This paper aims to investigate the differing structural deviation patterns among the three variants, and to what extent these discrepancies alter biochemical function relevant to the chronic pathogenicity of MS. Additionally, through the use of various open-source computational software—such as ColabFold (AlphaFold2) and UCSF ChimeraX's Matchmaker— as well as modern biological databases—such as UniProt and RCSB PDB—the paper deploys structural analysis on a molecular scale via comparative modeling. The paper supports a highlyconserved protein fold among all three variants, with increasing mutation-specific localized deviations (R415Q: 0.378 Å, P199H: 0.516 Å, S440C: 0.610 Å); furthermore, the paper highlights the R415Q mutation's exclusive presence and proximity (within 5 Å) to the RXR-binding interface, based on comparison to the solved LXRA-RXRβ crystal structure (1UHL), and supported by pLDDT/PAE/MSA coverage to distinguish computational uncertainty from genuine structural alteration. Ultimately, the paper offers a computational and structural analysis that distinguishes the R415Q variant's molecular significance regarding chronic MS from the other variants, amid modern scientific controversy and dispute. Moreover, the paper presents structural modeling and analysis as an efficacious triage tool.