# Identification and Characterization of an In Silico Designed Membrane‐Active Peptide with Antiviral Properties

## TL;DR

Scientists designed a peptide that can disrupt viral membranes and showed it works against several viruses, using a computational method called Evo-MD.

## Contribution

The paper introduces a novel in silico-designed peptide, P1.6, optimized to target lipid packing defects in viral membranes.

## Key findings

- P1.6 efficiently disrupts virus-like liposomes and inhibits HIV-1, Zika, and herpes simplex viruses without cytotoxicity.
- All-atom MD simulations and ATR-FTIR confirmed P1.6's α-helical structure and increased helicity upon membrane contact.
- Electron microscopy showed P1.6 causes envelope rupture and capsid release in HIV-1 particles.

## Abstract

Broad‐spectrum antivirals are urgently needed to counter emerging viral threats. Targeting the viral envelope, an essential, conserved, and host‐derived structure, offers a promising strategy with a low risk of resistance. Here, we report the in silico design and experimental characterization of P1.6, a 24‐mer peptide generated using an evolutionary molecular dynamics (Evo‐MD) platform and optimized to sense and exploit lipid packing defects in viral membranes. Among nine Evo‐MD–derived candidates, P1.6 showed the strongest membrane‐disruptive activity and inhibited HIV‐1, Zika virus, and herpes simplex viruses with IC50 values ranging from ∼0.06 to 3.5 µm. P1.6 efficiently disrupted virus‐like liposomes without causing cytotoxicity or hemolysis at antiviral concentrations. All‐atom MD simulations predicted a predominantly α‐helical solution structure with a central kink and flexible termini. Upon membrane engagement, this kink was largely lost, yielding a more continuous and stabilized helix. ATR‐FTIR spectroscopy confirmed the membrane‐induced increase in helicity. Coarse‐grained MD simulations further demonstrated that P1.6 stabilizes transient membrane pores, while electron microscopy of treated HIV‐1 particles revealed extensive envelope rupture and capsid release. Together, these results establish P1.6 as a potent membrane‐active antiviral lead and highlight the utility of Evo‐MD–guided peptide design to target conserved biophysical vulnerabilities in viral envelopes.

An evolutionary molecular dynamics platform is used to design P1.6, a membrane‐active peptide that senses lipid packing defects in viral envelopes. P1.6 adopts a stabilized α‐helical structure upon membrane contact, disrupts virus‐like liposomes, and damages HIV‐1 particles. This study highlights Evo‐MD–guided peptide engineering as a strategy for broad antiviral development.