DNA groove preference shift upon phosphorylation of a protamine-like cationic peptide

Protamines, arginine-rich DNA-binding proteins, are responsible for chromatin compaction in sperm cells, but their DNA groove preference, major or minor, is not clearly identified. We herein study the DNA groove preference of a short protamine-like cationic peptide before and after phosphorylation, using all-atom molecular dynamics and umbrella sampling simulations. According to various thermodynamic and structural analyses, a peptide in its non-phosphorylated native state prefers the minor groove over the major groove, but phosphorylation of the peptide bound to the minor groove not only reduces its binding affinity but also brings a serious deformation of the minor groove, eliminating the minor-groove preference. As protamines are heavily phosphorylated before binding to DNA, we expect that the structurally disordered phosphorylated protamines would prefer major grooves to enter into DNA during spermatogenesis. Entropic and Enthalpic contributions to Gibbs free energy of binding in four DNA-peptide complexes. It is observed that the binding of a protamine-like cationic peptide to DNA is enthalpy-driven for both major and minor grooves of DNA.

Automated summary

This study investigated the DNA groove preference of a short protamine-like cationic peptide before and after phosphorylation using molecular dynamics simulations. The results showed that the non-phosphorylated peptide preferred the minor groove, but phosphorylation reduced the binding affinity and deformed the minor groove. The binding of the peptide to DNA was enthalpy-driven.