Molecular dynamics simulations of peptides in aqueous nanodroplets and nanofilms

Abstract

Peptides in nanoscale aqueous environments are exposed to solvent conditions that are significantly different from those of bulk water. Using all-atom molecular dynamics (OPLS-AA/L, TIP4P/2005), we investigate five peptides—CBS-5, CBS-9, KKKDDD, DKDKDK, and GAD-1—in water nanodroplets (radius of approximately 2–3 nm) and nanofilms (thickness of approximately 5 nm), with bulk systems serving as references, across a temperature range of 180–300 K. The principal conclusion of this thesis is that temperature-dependent density changes and heterogeneities, surface water charge layering, and curvature affect the position, orientation, and secondary structure of peptides in aqueous nanoconfinement. We analyze the solvent structure through mass and charge density profiles for pure water nanodroplet and nanofilm systems. For droplet systems, we analyze peptide localization via radial distributions of Cα and charged sites, and water dynamics using a system-wise neighbour correlation function (NCF) and NCF resolved in concentric shells to derive a radial relaxation time τ(r). The peptide–droplet dynamics are assessed in comparison to the pure droplet using a normalized metric, τₙ(r). We compare the Cα and charged sites distributions in the nanodroplets with those in the nanofilms, and also analyze the pure bulk water and nanofilm using the mean square displacement and the system-wise NCF. Water in nanodroplets exhibits a neutral, slow-relaxing core and a charge-rich, more densely packed and faster-relaxing subsurface below around 240 K, and these density anomalies, as well as the radial dynamical heterogeneity, diminish upon warming. The location of peptides depends on both temperature and amino acid sequence: amphipathic GAD-1 and the hydrophobic CBS peptides preferentially sample the surface or subsurface, while charge-dense DK sequences favour the interior at higher temperatures and react to cooling. Charged regions in the nanodroplet subsurface affect the stabilization of charged amino acids. Above 240 K in nanodroplets, CBS- 9 maintains a polarized orientation of its termini (C-terminus inward, N-terminus outward) but its N-terminus shows bimodal distributions at lower temperature, while CBS-5 shows this orientation except at 300 K, where the termini occupy similar radial positions. The CBS peptides that are simulated in the nanofilm configurations across 180 K to 300 K also exhibit this polarization. Additionally, peptides can alter local water mobility; most notably, at 240 K, DK sequences inhibit relaxation close to their loci. With implications for electrospray, interfacial biophysics, and nanomedicine, these findings collectively paint a mechanistic picture of how peptide localization and conformational response are jointly governed by electrostatic confinement, curvature-dependent adsorption, and temperature-dependent solvent structural heterogeneity.