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Volume 27
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10.3390/ijms27188240
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Article

Molecular Dynamics Simulations Reveal Structural Changes Associated with the ABCA1 R230C Functional Variant

by
Juan José de la Cruz-López
1,
Luis Ramón Tercero Martínez-González
1,2,
Cecilia Albortante-Morato
3,
Rosaura Palma-Orozco
3,
María Teresa Flores-Dorantes
1,* and
Jorge Luis Rosas-Trigueros
3,*
1
Laboratorio de Biología Molecular y Farmacogenómica, Centro de Investigación de Ciencia y Tecnología Aplicada de Tabasco (CICTAT), División Académica de Ciencias Básicas (DACB), Universidad Juárez Autónoma de Tabasco (UJAT), Carretera Cunduacán-Jalpa de Méndez Km. 1, Cunduacán C.P. 86690, Tabasco, Mexico
2
División Académica de Ciencias y Tecnologías de la Información (DACYTI), Centro de Investigación de Ciencia y Tecnología Aplicada de Tabasco (CICTAT), Universidad Juárez Autónoma de Tabasco (UJAT), Carretera Cunduacán-Jalpa de Méndez Km. 1, Cunduacán C.P. 86690, Tabasco, Mexico
3
Laboratorio Transdisciplinario de Investigación en Sistemas Evolutivos, Escuela Superior de Cómputo (ESCOM), Instituto Politécnico Nacional (IPN), Ciudad de México 07738, Mexico
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2026, 27(18), 8240; https://doi.org/10.3390/ijms27188240
Submission received: 8 August 2026 / Revised: 8 September 2026 / Accepted: 14 September 2026 / Published: 16 September 2026
(This article belongs to the Special Issue Advances in Biophysical Studies on Lipid Membranes)
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Abstract

The ATP-binding cassette transporter A1 (ABCA1) functional variant R230C (rs9282541) is associated with low plasma HDL-C levels, yet its atomic-scale mechanism remains unclear. We evaluated the structural and dynamic impact of R230C compared to wild-type (WT) ABCA1 using 200 ns molecular dynamics simulations in a lipid raft membrane. While the tertiary fold was preserved, R230C exhibited reduced overall flexibility (lower RMSD and localized RMSF rigidification) alongside a slightly expanded conformation (increased Rg and SASA). Localized fluctuations near residue 230 in extracellular domain 1 (ECD1) were coupled with decreased dynamic heterogeneity in distal functional regions, particularly nucleotide-binding domain 2 (NBD2) and transmembrane domain 2 (TMD2). MOSAICS analysis revealed subtle alterations in membrane thickness, midplane displacement, and lipid orientation. Furthermore, CAVER tunnel analysis demonstrated increased pathway heterogeneity (17 clusters in R230C vs. 10 in WT), lower persistence, and smaller bottleneck radii, disrupting the primary cholesterol transport route. Thus, R230C acts as a dynamic allosteric modulator and membrane-coupling agent rather than a folding-disruptive mutation, providing a biophysical rationale for reduced cholesterol efflux and low plasma HDL-C levels.
Keywords: ABCA1 membrane protein; R230C variant; cholesterol efflux; HDL cholesterol; Protein Structure; hypoalphalipoproteinemia ABCA1 membrane protein; R230C variant; cholesterol efflux; HDL cholesterol; Protein Structure; hypoalphalipoproteinemia

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MDPI and ACS Style

de la Cruz-López, J.J.; Martínez-González, L.R.T.; Albortante-Morato, C.; Palma-Orozco, R.; Flores-Dorantes, M.T.; Rosas-Trigueros, J.L. Molecular Dynamics Simulations Reveal Structural Changes Associated with the ABCA1 R230C Functional Variant. Int. J. Mol. Sci. 2026, 27, 8240. https://doi.org/10.3390/ijms27188240

AMA Style

de la Cruz-López JJ, Martínez-González LRT, Albortante-Morato C, Palma-Orozco R, Flores-Dorantes MT, Rosas-Trigueros JL. Molecular Dynamics Simulations Reveal Structural Changes Associated with the ABCA1 R230C Functional Variant. International Journal of Molecular Sciences. 2026; 27(18):8240. https://doi.org/10.3390/ijms27188240

Chicago/Turabian Style

de la Cruz-López, Juan José, Luis Ramón Tercero Martínez-González, Cecilia Albortante-Morato, Rosaura Palma-Orozco, María Teresa Flores-Dorantes, and Jorge Luis Rosas-Trigueros. 2026. "Molecular Dynamics Simulations Reveal Structural Changes Associated with the ABCA1 R230C Functional Variant" International Journal of Molecular Sciences 27, no. 18: 8240. https://doi.org/10.3390/ijms27188240

APA Style

de la Cruz-López, J. J., Martínez-González, L. R. T., Albortante-Morato, C., Palma-Orozco, R., Flores-Dorantes, M. T., & Rosas-Trigueros, J. L. (2026). Molecular Dynamics Simulations Reveal Structural Changes Associated with the ABCA1 R230C Functional Variant. International Journal of Molecular Sciences, 27(18), 8240. https://doi.org/10.3390/ijms27188240

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