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Molecular dynamics simulations reveal structural differences among wild-type NPC1 protein and its mutant forms.

Authors
  • Martínez-Archundia, M1
  • Hernández Mojica, T G2
  • Correa-Basurto, J1
  • Montaño, S3
  • Camacho-Molina, A2
  • 1 Laboratorio de Modelado Molecular, Bioinformática y Diseño de fármacos, Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, México City, México.
  • 2 Departamento de Genética, Instituto Nacional de Neurología y Neurocirugía Manuel Velasco Suárez, Secretaría de Salud, Mexico City, México, Facultad de Ciencias Químico Biológicas. , (Mexico)
  • 3 Universidad Autónoma de Sinaloa, Culiacán, Sinaloa, México.
Type
Published Article
Journal
Journal of biomolecular structure & dynamics
Publication Date
Aug 01, 2020
Volume
38
Issue
12
Pages
3527–3532
Identifiers
DOI: 10.1080/07391102.2019.1664324
PMID: 31506030
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

NPC1 is a 25-exon gene located on the long arm of chromosome 18q11.2 and encodes NPC1, a transmembrane protein comprising 1278 amino acid residues. Mutations in the NPC1 gene can cause Niemann-Pick disease type C (NP-C), a rare autosomal-recessive neurovisceral disease. We assessed mutant protein folding using computer-based molecular dynamics (MD) simulations and molecular docking of the three most common NPC1 mutations, all of which result in changes in a cysteine-rich luminal loop region of the protein: a) I1061T is the most commonly detected variant in patients with NP-C worldwide; b) P1007A is the second most common variant, frequently detected in Portuguese, British and German patients; c) G992W occurs most often in patients of Acadian descent. Analyses of molecular structural information and related cellular physiological processes revealed that mutant NPC1 proteins exhibited altered function despite being far from the N-terminal domain cholesterol binding. MD simulations revealed that mutant I1061T protein shows remarkable instability in comparison the WT and also de other mutants, and interestingly this mutant has been identified as the most common variant. In the case of the mutant P1007A, it is presumed that this substitution promotes larger structural changes than proline due to their greater hydrophobic properties.Structural changes related to the G992W mutation may affect the physicochemical space of G992W variant protein because tryptophan induces hydrophobic interactions. Cholesterol docking studies focused on binding recognition showed differences in the binding positions of variants versus the wild-type protein that go some way to explaining the molecular pathogenesis.Communicated by Ramaswamy H. Sarma.

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