A molecular dynamics study of loop fluctuation in human papillomavirus type 16 virus-like particles: A possible indicator of immunogenicity

Joshi, Harshad; Cheluvaraja, Srinath; Somogyi, E; Brown, Darron R.; Ortoleva, P.

doi:10.1016/j.vaccine.2011.10.039

Cited by 29 publications

(41 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…49 Furthermore, weakly organized VLP assemblies are found to be less immunogenic than more tightly packed ones. 52 One explanation of these observations comes from the fluctuation-immunogenicity hypothesis: To illicit proper immune response, epitope fluctuations must be minimized, 40 such that the epitope structures are better defined and rigid over time; in tightly packed VLPs the epitope fluctuations are less pronounced than those in smaller systems. In other words, simply presenting an epitope to the immune system is not enough, as the structural fluctuations may render them unrecognizable.…”

Section: ■ Introductionmentioning

confidence: 99%

Epitope Fluctuations in the Human Papillomavirus Are Under Dynamic Allosteric Control: A Computational Evaluation of a New Vaccine Design Strategy

et al. 2013

Self Cite

View full text Add to dashboard Cite

The dynamic properties of the capsid of the human papillomavirus (HPV) type 16 were examined using classical molecular dynamics simulations. By systematically comparing the structural fluctuations of the capsid protein, a strong dynamic allosteric connection between the epitope containing loops and the h4 helix located more than 50 Å away is identified, which was not recognized thus far. Computer simulations show that restricting the structural fluctuations of the h4 helix is key to rigidifying the epitopes, which is thought to be required for eliciting a proper immune response. The allostery identified in the components of the HPV is nonclassical because the mean structure of the epitope carrying loops remains unchanged, but as a result of allosteric effect the structural fluctuations are altered significantly, which in turn changes the biochemical reactivity profile of the epitopes. Exploiting this novel insight, a new vaccine design strategy is proposed wherein a relatively small virus capsid fragment is deposited on a silica nanoparticle in such a way that the fluctuations of the h4 helix are suppressed. The structural and dynamic properties of the epitope carrying loops on this hybrid nanoparticle match the characteristics of epitopes found on the full virus-like particle precisely, suggesting that these nanoparticles may serve as potent, cost-effective, and safe alternatives to traditionally developed vaccines. The structural and dynamic properties of the hybrid nanoparticle are examined in detail to establish the general concepts of the proposed new design.

show abstract

Section: ■ Introductionmentioning

confidence: 99%

Epitope Fluctuations in the Human Papillomavirus Are Under Dynamic Allosteric Control: A Computational Evaluation of a New Vaccine Design Strategy

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…15 For the HPV-neutralizing mAbs for which epitopes have been identified, the immuno dominant epitopes have been shown to localize in the different flexible loops on the VLP surface (Table 3 and Fig. 4) [84][85][86] . Therefore, the correct spatial conformation of these loops and the structural integrity of the VLPs are essential for inducing effective neutralizing antibodies for vaccine efficacy.…”

Section: Hpv Vaccine and The Key Epitopes On Vlpsmentioning

confidence: 99%

Lessons learned from successful human vaccines: Delineating key epitopes by dissecting the capsid proteins

Zhang

et al. 2015

Human Vaccines & Immunotherapeutics

View full text Add to dashboard Cite

Recombinant VLP-based vaccines have been successfully used against 3 diseases caused by viral infections: Hepatitis B, cervical cancer and hepatitis E. The VLP approach is attracting increasing attention in vaccine design and development for human and veterinary use. This review summarizes the clinically relevant epitopes on the VLP antigens in successful human vaccines. These virion-like epitopes, which can be delineated with molecular biology, cryo-electron microscopy and x-ray crystallographic methods, are the prerequisites for these efficacious vaccines to elicit functional antibodies. The critical epitopes and key factors influencing these epitopes are discussed for the HEV, HPV and HBV vaccines. A pentamer (for HPV) or a dimer (for HEV and HBV), rather than a monomer, is the basic building block harboring critical epitopes for the assembly of VLP antigen. The processing and formulation of VLP-based vaccines need to be developed to promote the formation and stabilization of these epitopes in the recombinant antigens. Delineating the critical epitopes is essential for antigen design in the early phase of vaccine development and for critical quality attribute analysis in the commercial phase of vaccine manufacturing.

show abstract

“…An inverse correlation between MSF and immunogenicity was hypothesized for HPV VLPs and possibly for other systems [11,44].…”

Section: Mean Square Fluctuationsmentioning

confidence: 99%

“…In computational studies of HPV VLPs, the intensity of fluctuations expressed by epitopes decreased across monomers, pentamers, and VLPs, respectively [11]. Moreover, the degree of epitope fluctuation was observed to have an inverse relationship with antibody binding energy in flaviviruses [12].…”

Section: Introductionmentioning

confidence: 98%

“…Here, the epitope fluctuation−immunogenicity hypothesis [11,22]-a proposed inverse correlation between immunogenicity and epitope fluctuation intensity-is assessed using a spectrum of nonenveloped viruses. This study represents the first attempt to link computationally predicted molecular properties and experimentally derived immunogenicity for a spectrum of viruses.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Broad spectrum assessment of the epitope fluctuation—Immunogenicity hypothesis

Grosch

Yang

Shen

et al. 2015

Vaccine

View full text Add to dashboard Cite

A molecular dynamics study of loop fluctuation in human papillomavirus type 16 virus-like particles: A possible indicator of immunogenicity

Cited by 29 publications

References 38 publications

Epitope Fluctuations in the Human Papillomavirus Are Under Dynamic Allosteric Control: A Computational Evaluation of a New Vaccine Design Strategy

Epitope Fluctuations in the Human Papillomavirus Are Under Dynamic Allosteric Control: A Computational Evaluation of a New Vaccine Design Strategy

Lessons learned from successful human vaccines: Delineating key epitopes by dissecting the capsid proteins

Broad spectrum assessment of the epitope fluctuation—Immunogenicity hypothesis

Contact Info

Product

Resources

About