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Grant support

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.

Analysis of institutional authors

Escrig, JudithAuthorDominguez-Zotes, SantosAuthorValbuena, AlejandroCorresponding AuthorMateu, Mauricio GCorresponding Author

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October 14, 2024
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Structural Basis for Alternative Self-Assembly Pathways Leading to Different Human Immunodeficiency Virus Capsid-Like Nanoparticles

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

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

Affiliations

mAbxience Genhelix, Julia Morros S-N, Leon 24009, Spain - Author
UAM, CSIC, Ctr Biol Mol Severo Ochoa, Bioinformat Unit, Campus Univ Autonoma Madrid, Madrid 28049, Spain - Author
UAM, CSIC, Ctr Biol Mol Severo Ochoa, Mol Modeling Grp, Madrid 28049, Spain - Author
UAM, CSIC, Virus Engn Grp, Ctr Biol Mol Severo Ochoa, Madrid 28049, Spain - Author

Abstract

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.

Keywords

ArchitectureAssembly pathwaysCapsidCapsid proteinsGrowthHiv-1HumansInterfacModelModels, molecularMolecular dynamicMolecular dynamicsMolecular dynamics simulationMolecular-dynamicsMutational analysisMutationalanalysisNanoparticleNanoparticlesNucleationParticlesProteinRevealSelf-assemblySufficientTerminal domainVirus capsid

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal ACS Nano due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2024 there are still no calculated indicators, but in 2023, it was in position 14/178, thus managing to position itself as a Q1 (Primer Cuartil), in the category Chemistry, Physical. Notably, the journal is positioned above the 90th percentile.

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-06:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 2.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 2 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 1.
  • The number of mentions on the social network X (formerly Twitter): 1 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

Leadership analysis of institutional authors

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: First Author (ESCRIG TRAVER, JUDITH) and Last Author (GARCIA MATEU, MAURICIO).

the authors responsible for correspondence tasks have been VALBUENA JIMENEZ, ALEJANDRO and GARCIA MATEU, MAURICIO.