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The surface properties of biologically active nanoparticles (NPs) are often dictated by synthetic ligands that are grafted to the NP core to form a protecting monolayer. Ligand selection is thus critical in determining NP surface properties and corresponding interactions at the nano-bio interface, which are relevant to numerous applications including drug delivery and biosensing. However, chemically specific structure–property relationships for rationally selecting ligands to achieve desired biointeractions are largely lacking. In this Focus Article, we review the challenges associated with relating ligand chemical properties to monolayer-protected NP surface properties due to the interplay of ligand–ligand, ligand–solvent, and ligand–biomolecule interactions that are difficult to anticipate. In particular, we highlight unexpected spatially varying properties that emerge even for uniformly functionalized NPs due to the fluctuations of ligands at the nanoscale. We further review the capability of physics-based molecular simulations to reveal these unexpected behaviors, providing powerful computational methods to predict NP properties. Finally, we discuss the opportunity for such simulations to be combined with machine-learning methods to guide the computational design of monolayer-protected NPs prior to synthesis. 

The orientation of integral membrane proteins (IMPs) with respect to the membrane is established during protein synthesis and insertion into the membrane. After synthesis, IMP orientation is thought to be fixed due to the thermodynamic barrier for “flipping” protein loops or helices across the hydrophobic core of the membrane in a process analogous to lipid flip-flop. A notable exception is EmrE, a homodimeric IMP with an N-terminal transmembrane helix that can flip across the membrane until flipping is arrested upon dimerization. Understanding the features of the EmrE sequence that permit this unusual flipping behavior would be valuable for guiding the design of synthetic materials capable of translocating or flipping charged groups across lipid membranes. To elucidate the molecular mechanisms underlying flipping in EmrE and derive bioinspired design rules, we employ atomistic molecular dynamics simulations and enhanced sampling techniques to systematically investigate the flipping of truncated segments of EmrE. Our results demonstrate that a membrane-exposed charged glutamate residue at the center of the N-terminal helix lowers the energetic barrier for flipping (from ~12.1 kcal mol-1 to ~5.4 kcal mol-1) by stabilizing water defects and minimizing membrane perturbation. Comparative analysis reveals that the marginal hydrophobicity of this helix, rather than the marginal hydrophilicity of its loop, is the key determinant of flipping propensity. Our results further indicate that interhelical hydrogen bonding upon dimerization inhibits flipping. These findings establish several bioinspired design principles to govern flipping in related materials: (1) marginally hydrophobic helices with membrane-exposed charged groups promote flipping, (2) modulating protonation states of membrane-exposed groups tunes flipping efficiency, and (3) interhelical hydrogen bonding can be leveraged to arrest flipping. These insights provide a foundation for engineering synthetic peptides, engineered proteins, and biomimetic nanomaterials with controlled flipping or translocation behavior for applications in intracellular drug delivery and membrane protein design. 

We utilize coarse-grained molecular dynamics simulations and enhanced sampling methods to reveal the effect of ligand branching on the thermodynamics of nanoparticle adsorption to lipid bilayers.