Protamine-Controlled Reversible DNA Packaging: A Molecular Glue

Abstract

Packaging paternal genome into tiny sperm nuclei during spermatogenesis requires 10 6 -fold compaction of DNA, corresponding to a 10−20 times higher compaction than in somatic cells. While such a high level of compaction involves protamine, a small arginine-rich basic protein, the precise mechanism at play is still unclear. Effective pair potential calculations and large-scale molecular dynamics simulations using a simple idealized model incorporating solely electrostatic and steric interactions clearly demonstrate a reversible control on DNA condensates formation by varying the protamine-to-DNA ratio. Microscopic states and condensate structures occurring in semidilute solutions of short DNA fragments are in good agreement with experimental phase diagram and cryoTEM observations. The reversible microscopic mechanisms induced by protamination modulation should provide valuable information to improve a mechanistic understanding of early and intermediate stages of spermatogenesis where an interplay between condensation and liquid−liquid phase separation triggered by protamine expression and post-translational regulation might occur. Moreover, recent vaccines to prevent virus infections and cancers using protamine as a packaging and depackaging agent might be fine-tuned for improved efficiency using a protamination control.

Formation of Protamine and Zn–Insulin Assembly: Exploring Biophysical Consequences

“…Previously, protamine was shown to have a tendency to condense/aggregate DNA by sequestering it in the form of ordered aggregates. 24 , 53 ITC suggesting the possibility of multiple insulin molecules binding to the protamine chain is consistent with this picture of how such condensation of insulin can occur in the presence of protamine. We assume that this is an ordered condensation and not aggregation or precipitation, as the data (AFM and ThT fluorescence) clearly do not support the latter.…”

Probing the hierarchical dynamics of DNA-sperm nuclear transition protein complex through fuzzy interaction and mesoscale condensation

“…Interestingly, when excess TNP1 were added, the TNP1-DNA mixture returns to a disperse state with only small bundles. These kinds of reversibly assembly and disassembly phenomenon have been observed in protamine-mediated DNA assembly as well as RNA-peptide/protein condensates (Banerjee et al, 2017; Henninger et al, 2021; Mukherjee et al, 2021a).…”

“…No rotation restraints were applied to the TNP1 peptide, giving full flexibility to TNP1 molecules. Detailed parameter set-up for DNA, TNP1, and counter ions (Na+ and Cl-) could refer to the study of Mukhejee and coworkers (Mukherjee et al, 2021a).…”

Biomimetic Nanoparticle-Mediated Target Delivery of Hypoxia-Responsive Plasmid of Angiotensin-Converting Enzyme 2 to Reverse Hypoxic Pulmonary Hypertension

“…Therefore, ACE2 is an ideal target for gene therapy of HPH. However, the naked gene is electronegative, has a large molecular weight, is difficult to reach the target site, and has a short half-life in vivo . In addition, the negative charged gene results in very low efficiency of cellular uptake, directly reducing the therapeutic effect.…”

“…However, the naked gene is electronegative, has a large molecular weight, is difficult to reach the target site, and has a short half-life in vivo. 18 In addition, the negative charged gene results in very low efficiency of cellular uptake, directly reducing the therapeutic effect. Although a viral-vector-based gene delivery system shows high transduction efficiency in vivo, it may result in the off-target modification of the genome, with risks of mutagenesis and carcinogenesis and immune rejection response.…”