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International Journal of Biological Macromolecules

International Journal of Biological Macromolecules

IF: 7.7
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Investigating the stability of chimeric murine polyomavirus VP1 Capsomeres via molecular dynamics simulations and experimental analysis

Published:4 December 2024 DOI: 10.1016/j.ijbiomac.2024.138372 PMID: 39643186
Hong Luo,?Yanyan Ma,?Zhiguo Su,?Yanhao Gu,?Songping Zhang,?Lukas Gerstweiler

Abstract

The development of modular virus-like particle (VLP) vaccine platforms with genetically inserted antigens in viral structural proteins shows great promise for advancing vaccine technology. However, the instability of many constructs leads to trial-and-error approaches, and the challenge of predicting stability based solely on amino acid sequences remains unresolved, yet highly appealing. This study evaluates the stability of wild-type murine polyomavirus (MPV) VP1 capsomeres and three engineered chimeric variants using molecular dynamics (MD) simulations and laboratory experiments. MD simulations, based on AlphaFold2 predictions and up-to-date all-atom force fields, accurately predicted the thermal stability and hydrophobicity of VP1-based capsomeres. Thermodynamic analysis revealed that binding energies from simulations reliably indicate thermal stability. Experiments and simulation results showed that inserts influence the stability of capsomeres differently, with larger insertions generally having a greater impact on the structures of capsomeres. This leads to increased intra-subunit distances and a higher proportion of flexible regions in the capsomere chassis. Capsomeres with less compact structures were found to have lower thermal stability. Specifically, the thermal transitional temperature (Tm) of the wild-type capsomeres was 46.9?°C, while the Tm values of the three chimeric derivatives were 42.0?°C, 38.8?°C, and 37.7?°C, reflecting a correlation between decreased thermal stability and reduced structural compactness. This research presents a robust approach for predicting the stability of novel VLP constructs based on amino acid sequences, potentially enhancing vaccine design by reducing failures, and suggests a shift towards minimal epitope insertions for improved stability.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Glycerol 56-81-5 C3H8O3 2085 suppliers $5.00-$6250.00
Sodium chloride 7647-14-5 ClNa 1566 suppliers $5.00-$6678.62
Potassium Phosphate Monobasic 7778-77-0 H2KO4P 1110 suppliers $9.00-$7640.00
IPTG 367-93-1 C9H18O5S 1080 suppliers $5.00-$30622.00
Agar 9002-18-0 C14H24O9 776 suppliers $14.00-$4338.01
Potassium Phosphate Dibasic 7758-11-4 K2HPO4 743 suppliers $17.47-$6594.00
Yeast extract 8013-01-2 n.a. 537 suppliers $31.00-$7970.00
PEPTONE 91079-83-3 79 suppliers $108.00-$189.00