Year: 2026
Type: preprint
Abstract: Peptide-based polyelectrolyte complexes (PECs) are a promising class of stimuli-responsive materials with applications in drug delivery. Yet, the molecular mechanism by which stereochemical patterning governs their phase behavior remains unresolved. Racemic chiral patterning is known to favor liquid coacervate formation over solid precipitation by disrupting the ordered β-sheet structure, but experimentally elucidating the molecular-level origin of the solution-phase selection remains challenging. Coarse-grained (CG) molecular dynamics simulations offer a practical route to accessing the time and length scales relevant to coacervate phase behavior but require force fields that capture sequence-dependent structural propensities. One of them is chirality, a capability that has not previously been validated for peptide-based PEC systems. Here, we expand the SIRAH CG force field for modeling chirally and hydrophobically patterned peptide-based PEC systems. By introducing D-chiral dihedral parameters, achieved by inverting the phase angles of the SIRAH backbone torsion potential, we simulate both racemic and homochiral variants of six model PEC systems and compare the results to microsecond atomistic C36m simulations and published FTIR secondary structure data. The racemic SIRAH model reproduces atomistic trends in peptide compaction, aggregate density, and interfacial structure, as assessed by radius of gyration distributions, radial density profiles, and hyperbolic-tangent fits to the droplet interface. Racemic systems exhibit higher backbone contact counts and greater peptide compaction than their homochiral counterparts, consistent with the formation of dense, disordered aggregates characteristic of the liquid coacervate phase, where chains maintain close contact without adopting long-range β-sheet order. These results provide molecular-level support for the macroscopic observation that racemic patterning favors coacervate over precipitate formation, and reveal that alternating chirality promotes compact, entangled chain conformations that satisfy backbone hydrogen bonding outside of canonical β-sheet structures rather than simply eliminating it, a mechanism beyond β-sheet disruption alone. Hydrophobicity-dependent trends in secondary structure and solvent exposure are well reproduced regardless of chiral patterning, establishing SIRAH as a viable framework for peptide-based coacervate simulations and identifying stereochemical patterning as an independent sequence-specific route for tuning coacervate density. Because the SIRAH protein and nucleic acid parameters were derived within a single, structurally consistent framework, the same approach extends naturally to peptide–nucleic acid complex coacervates, an assembly class of growing interest for delivery applications and one that few coarse-grained force fields can treat at backbone-level resolution.
Source: ChemRxiv
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: G1301472186, MRI: Acquisition of a high-performance computing resource to enhance research and undergraduate education at the College of Staten Island, G4870198231, Nanoscience Connected to Life: An Interdisciplinary Traineeship Program in Bioinspired Nanotechnology, CAREER: Designing a Synthetic Nucleolus for Cell Free Biocatalysis
OpenAlex ID: W7214107814