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This work was funded by grants to M.G.M. (MICINN/FEDER EU RTI2018-096635-B-I00 and PID2021-126973OB-I00) and to P.G.-P (MCIU-AEI RTI2018-094434-B-I00 and MICINN FEDER EU PID2021-126625OB-I00/10.13039/501100011033/), and benefitted also from institutional grants from the Severo Ochoa Program for Centers of Excellence in R&D (CEX2021-00154-S) and Fundacion Ramon Areces to the Centro de Biologia Molecular Severo Ochoa. M.G.M. is an associate member of the Institute for Biocomputation and Physics of Complex Systems, Zaragoza, Spain.

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Structural Basis for Alternative Self-Assembly Pathways Leading to Different Human Immunodeficiency Virus Capsid-Like Nanoparticles

Publicado en:ACS Nano. 18 (40): 27465-27478 - 2024-09-27 18(40), DOI: 10.1021/acsnano.4c07948

Autores: Escrig, Judith; Marcos-Alcalde, Inigo; Dominguez-Zotes, Santos; Abia, David; Gomez-Puertas, Paulino; Valbuena, Alejandro; Mateu, Mauricio G

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Resumen

The mechanisms that underlie the spontaneous and faithful assembly of virus particles are guiding the design of self-assembling protein-based nanostructures for biomedical or nanotechnological uses. In this study, the human immunodeficiency virus (HIV-1) capsid was used as a model to investigate what molecular feature(s) may determine whether a protein nanoparticle with the intended architecture, instead of an aberrant particle, will be self-assembled in vitro. Attempts of using the HIV-1 capsid protein CA for achieving in vitro the self-assembly of cone-shaped nanoparticles that contain CA hexamers and pentamers, similar to authentic viral capsids, had typically yielded hexamer-only tubular particles. We hypothesized that a reduction in the stability of a transient major assembly intermediate, a trimer of CA dimers (ToD), will increase the propensity of CA to assemble in vitro into cone-shaped particles instead of tubes. Certain amino acid substitutions at CA-CA interfaces strongly favored in vitro the assembly of cone-shaped nanoparticles that resembled authentic HIV-1 capsids. All-atom MD simulations indicated that ToDs formed by CA mutants with increased propensity for assembly into cone-shaped particles are destabilized relative to ToDs formed by wt CA or by another mutant that assembles into tubes. The results also indicated that ToD destabilization is mediated by conformational distortion of different CA-CA interfaces, which removes some interprotein interactions within the ToD. A model is proposed to rationalize the linkage between reduced ToD stability and increased propensity for the formation of CA pentamers during particle growth in vitro, favoring the assembly of cone-shaped HIV-1 capsid-like nanoparticles.

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