Cholesterol Conjugated Elastin-like Recombinamers: Molecular Dynamics Simulations, Conformational Changes, and Bioactivity.

Pablo Taboada, Rui L Reis, Gerardo Prieto, Rui R Costa, Vicente Domínguez-Arca, Brenda Velasco, José Carlos Rodríguez-Cabello, Iva Pashkuleva

Journal: ACS applied materials & interfaces 2024;16(48):66327-66340

PMID: 39561189

Full Text on American Chemical Society View on PubMed

Abstract

Current models for elastin-like recombinamer (ELR) design struggle to predict the effects of nonprotein fused materials on polypeptide conformation and temperature-responsive properties. To address this shortage, we investigated the novel functionalization of ELRs with cholesterol (CTA). We employed GROMACS computational molecular dynamic simulations complemented with experimental evidence to validate the predictions. The ELR was biosynthesized and characterized by using fluorescence assays, circular dichroism, dynamic light scattering, and differential scanning calorimetry. The and data showed that CTA promotes the formation of intramolecular hydrogen bonds that favor β-sheet secondary structures. Compared with an unmodified ELR, CTA enhanced the hydrophobicity and stability of the system, allowing the formation of monodisperse nanoaggregates at physiologically relevant temperatures. Importantly, calorimetry assays revealed that ELR interacted and intercalated with the lipid bilayers of the DPPC liposomes. To demonstrate the implications of these changes for biomedical applications, ELR and DPPC-ELR hybrid nanoparticles were tested with cancer and immune cell lines. Interactions with the cell membranes demonstrated a synergistic effect of the composition and size of the modified recombinamer aggregates on the internalization. The results indicated the potential use of ELR-based nanoparticles for localized and systemic drug delivery. This work sets a new precedent to design elastin-inspired biomaterials with predictable self-assembly properties and develop novel drug delivery strategies.

Address: 3B's Research Group, I3Bs─Research Institute on Biomaterials, Biodegradables, and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-694 Barco, Guimarães, Portugal.; ICVS/3B's, PT Government Associate Laboratory, 4805-694 Braga, Guimarães, Portugal.; Colloids and Polymers Physics Group, Department of Applied Physics, Faculty of Physics and Institute of Materials (iMATUS) and Institute of Health Research (IDIS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.; Biosystems and Bioprocess Engineering (Bio2Eng) Group, Institute of Marine Research of Spanish Research Council, IIM-CSIC, 36208 Vigo, Spain.; Colloids Physical and Biophysical Chemistry, Bielefeld University, Universitätsstr. 25, Bielefeld 33615, Germany.; Colloids and Polymers Physics Group, Department of Applied Physics, Faculty of Physics and Institute of Materials (iMATUS) and Institute of Health Research (IDIS), University of Santiago de Compostela, 15782 Santiago de Compostela, Spain.; 3B's Research Group, I3Bs─Research Institute on Biomaterials, Biodegradables, and Biomimetics, University of Minho, Headquarters of the European Institute of Excellence on Tissue Engineering and Regenerative Medicine, AvePark, Parque de Ciência e Tecnologia, Zona Industrial da Gandra, 4805-694 Barco, Guimarães, Portugal.; ICVS/3B's, PT Government Associate Laboratory, 4805-694 Braga, Guimarães, Portugal.; Bioforge Lab, Group for Advanced Materials and Nanobiotechnology, Biomedical Networking Research Center of Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Edificio LUCIA, Universidad de Valladolid, 47011 Valladolid, Spain.

DOI: 10.1021/acsami.4c07285

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MeSH Terms: Elastin, Molecular Dynamics Simulation, Cholesterol, Humans, Nanoparticles, Lipid Bilayers, Hydrophobic and Hydrophilic Interactions