Bernardes Santana Martins, I.

bioRxiv2025

Synergistic Effects of pH and Temperature on Dengue VirusEnvelope Dimers: Insights from Microsecond MolecularDynamics Simulations

Dengue pathogenesis depends on a conformational rearrangement of the envelope (E) glycoprotein induced by low pH; however, how pH and temperature cooperate to destabilize its prefusion dimeric state, a fundamental step that enables the formation of the fusion-active trimer, remains unclear. Here, we investigate this synergy for Dengue serotypes of greatest medical relevance, DENV-2 and DENV-3. All-atom molecular dynamics simulations were performed on the microsecond scale, at 28 {degrees}C, 37 {degrees}C, and 40 {degrees}C under pH 5-7, using CHARMM36m force fields. The increase in temperature from 28 {degrees}C to 37 {degrees}C doubled the conformational space explored at neutral pH and weakened both dimers through the reduction or loss of the interaction network along the dimeric interface. Acidification amplified this effect in a serotype-specific manner: DENV-2 required pH 5, while DENV-3 responded at pH 6. Distance and principal component analyses revealed an asymmetric dissociation route, termed the "compensatory embrace", in which retraction of Domains I and III in one monomer is balanced by advancement of its partner on the opposite side, temporarily preserving the number of inter-subunit contacts. Structural analyses highlighted the difference in histidine distribution between the serotypes. These results outline hierarchical physicochemical triggers that convert the dimer into fusion-competent monomers. Targeting the interfacial interaction network or reinforcing the "compensatory embrace" to prevent completion of dissociation offers new perspectives for broad-spectrum antivirals and immunogen design, underscoring the value of long-timescale molecular dynamics in drug discovery.

biophysics↗

bioRxiv2020

The effect of acidic pH on the interaction and lytic activity of MP1 and its H-MP1 analog in anionic lipid membrane: a biophysical study by Molecular Dynamics and Spectroscopy

Antimicrobial peptides (AMPs) are part of the innate immune system of many species and are compounds with potential application against the development of resistant bacterial strains promoted by conventional antibiotics. The AMPs are rich in cationic and hydrophobic residues and act directly on the lipidic phase of the cell membranes. The MP1 has a broad-spectrum bactericide activity in both Gram-negative and positive bacteria, not being hemolytic or cytotoxic. H-MP1 is a synthetic analog of MP1 with lysines replaced by histidines so that its net charge could be responsive to changes in solution pH. In the present work, we investigated the effect of the solution pH on the structural properties, in the adsorption and insertion, and on the lytic activity of these peptides in lipid bilayers mimicking the cell membrane of Gram-negative bacteria, using experimental and computational biophysical techniques. The results indicate that the lytic activity of H-MP1 is sensitive to pH, increasing to an acidic environment, matching that of MP1, which is not influenced by solution pH. Molecular Dynamic simulations indicated that the adsorption process of both peptides started by the interaction of the N-terminus with the bilayer, followed by the complete adsorption of the peptide laying parallel to the bilayer plane, inducing an increase in the peptides helical content enhancing peptides contact with the bilayer hydrophobic phase.

biophysics↗