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Efficient Quantification of Lipid Packing Defect Sensing by Amphipathic Peptides: Comparing Martini 2 and 3 with CHARMM36.

ABSTRACT: In biological systems, proteins can be attracted to curved or stretched regions of lipid bilayers by sensing hydrophobic defects in the lipid packing on the membrane surface. Here, we present an efficient end-state free energy calculation method to quantify such sensing in molecular dynamics simulations. We illustrate that lipid packing defect sensing can be defined as the difference in mechanical work required to stretch a membrane with and without a peptide bound to the surface. We also demonstrate that a peptide's ability to concurrently induce excess leaflet area (tension) and elastic softening─a property we call the "characteristic area of sensing" (CHAOS)─and lipid packing sensing behavior are in fact two sides of the same coin. In essence, defect sensing displays a peptide's propensity to generate tension. The here-proposed mechanical pathway is equally accurate yet, computationally, about 40 times less costly than the commonly used alchemical pathway (thermodynamic integration), allowing for more feasible free energy calculations in atomistic simulations. This enabled us to directly compare the Martini 2 and 3 coarse-grained and the CHARMM36 atomistic force fields in terms of relative binding free energies for six representative peptides including the curvature sensor ALPS and two antiviral amphipathic helices (AH). We observed that Martini 3 qualitatively reproduces experimental trends while producing substantially lower (relative) binding free energies and shallower membrane insertion depths compared to atomistic simulations. In contrast, Martini 2 tends to overestimate (relative) binding free energies. Finally, we offer a glimpse into how our end-state-based free energy method can enable the inverse design of optimal lipid packing defect sensing peptides when used in conjunction with our recently developed evolutionary molecular dynamics (Evo-MD) method. We argue that these optimized defect sensors─aside from their biomedical and biophysical relevance─can provide valuable targets for the development of lipid force fields.

SUBMITTER: van Hilten N

PROVIDER: S-EPMC9281404 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The evolution of bonded restorations has undergone great progress over several decades. Nonetheless, life spans of bonded restorations are limited mainly because of the eventual incidence of recurrent caries. Over time, water and waterborne agents (acids, enzymes) degrade the components of the dentin/restoration interface, allowing bacterial colonization and dentin reinfection at the margins of the restoration. We developed a 2-tier protective technology consisting of priming/coating dentin with amphipathic and antimicrobial peptides (AAMPs) to obtain hydrophobic/water-repellent and antibiofilm dentin-resisting recurrent caries around bonded restorations. We tested a series of AAMPs to assess their structure-function relationships as well as the effects of different dentin-conditioning methods on the structural features of AAMP-coated dentin. We found relation between the secondary structure of AAMPs (high portion of β-sheet), the antimicrobial potency of AAMPs, and the AAMPs' ability to form hydrophobic coatings on dentin. We also determined that AAMPs had preferential adsorption on the mineral phase of dentin, which suggested that peptides arrange their cationic and hydrophilic motifs in direct contact with the negatively charged minerals in the hydrophilic dentin. These results led us to explore different dentin-conditioning methods that would increase the mineral/collagen ratio and their effect on AAMP immobilization. We innovatively imaged the spatial distribution of the AAMPs in relation to the dentinal tubules and collagen network using a minimally invasive multimodal imaging technique: multiphoton-second harmonic generation. Using multiphoton-second harmonic generation imaging, we determined that partial deproteinization of dentin increased the amount of immobilized AAMPs as compared with the total etched dentin at the dentin surface and extended deeply around dentinal tubules. Last, we analyzed the release rate of AAMPs from dentin coatings in artificial saliva to predict their stability in the clinical setting. In conclusion, priming dentin with AAMPs is a versatile new approach with potential to fortify the otherwise vulnerable adhesive-based interfaces.

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Efficient Quantification of Lipid Packing Defect Sensing by Amphipathic Peptides: Comparing Martini 2 and 3 with CHARMM36.

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