Computational Analysis of Wild-Type and I143T Mutant PSEN1: Molecular Docking Reveals Reduced PC1 Ligand Binding Affinity in Early-Onset Familial Alzheimer's Disease

Abstract

Background: Presenilin-1 (PSEN1) mutations are frequently associated with early-onset familial Alzheimer's disease (EOAD), a progressive neurodegenerative disorder. The PSEN1 I143T variant has been implicated in disease pathogenesis; however, its potential structural and molecular effects on ligand binding require further investigation.

Methods: Gene–disease association analysis was performed using overlapping datasets from DisGeNET and GeneCards, identifying PSEN1 as a significant candidate gene. Three-dimensional structural models of wild-type and I143T mutant PSEN1 were generated using AlphaFold. Molecular docking of the PC1 ligand against both protein forms was performed using the Molecular Operating Environment (MOE) software. Binding energies, estimated dissociation constants (Kd), and protein–ligand interactions were subsequently compared between the wild-type and mutant structures.

Results: The I143T mutant demonstrated reduced binding affinity for PC1 compared with wild-type PSEN1. The mutant exhibited a minimum binding energy of −7.8 kcal/mol (mean: −5.7 ± 0.9 kcal/mol), corresponding to an estimated Kd of 2.1 μM, whereas wild-type PSEN1 showed a minimum binding energy of −8.4 kcal/mol (mean: −6.2 ± 0.9 kcal/mol), corresponding to a Kd of 0.7 μM. Analysis of protein–ligand interactions revealed the loss of hydrophobic interactions involving residue 143 in the mutant. Additionally, the hydrogen-bond distance between PC1 and Ser169 increased from 2.8 Å in the wild-type protein to 3.0 Å in the I143T mutant. Neither the wild-type nor mutant PSEN1 demonstrated direct interactions between PC1 and the catalytic aspartate residues Asp257 or Asp385.

Conclusion: The PSEN1 I143T mutation was associated with reduced PC1 binding affinity and localized alterations in protein–ligand interactions. The loss of hydrophobic interactions at residue 143 and increased hydrogen-bond distance with Ser169 suggest that the mutation may induce localized conformational changes that affect ligand binding. These findings provide computational evidence supporting the potential functional and pathogenic significance of the I143T variant in early-onset Alzheimer's disease.