Long-Chain Lipids Facilitate Insertion of Large Nanoparticles into Membranes of Small Unilamellar Vesicles.

Insertion of hydrophobic nanoparticles into phospholipid bilayers is limited to small particles that can incorporate into a hydrophobic membrane core between two lipid leaflets. Incorporation of nanoparticles above this size limit requires the development of challenging surface engineering methodologies. In principle, increasing the long-chain lipid component in the lipid mixture should facilitate incorporation of larger nanoparticles. Here, we explore the effect of incorporating very long phospholipids (C24:1) into small unilamellar vesicles on the membrane insertion efficiency of hydrophobic nanoparticles that are 5-11 nm in diameter. To this end, we improve an existing vesicle preparation protocol and utilized cryogenic electron microscopy imaging to examine the mode of interaction and evaluate the insertion efficiency of membrane-inserted nanoparticles. We also perform classical coarse-grained molecular dynamics simulations to identify changes in lipid membrane structural properties that may increase insertion efficiency. Our results indicate that long-chain lipids increase the insertion efficiency by preferentially accumulating near membrane-inserted nanoparticles to reduce the thermodynamically unfavorable disruption of the membrane.

Interactions of Bacterial Quorum Sensing Signals with Model Lipid Membranes: Influence of Membrane Composition on Membrane Remodeling.

We report the influence of membrane composition on the multiscale remodeling of multicomponent lipid bilayers initiated by contact with the amphiphilic bacterial quorum sensing signal N-(3-oxo)-dodecanoyl-l-homoserine lactone (3-oxo-C12-AHL) and its anionic headgroup hydrolysis product, 3-oxo-C12-HS. We used fluorescence microscopy and quartz crystal microbalance with dissipation (QCM-D) to characterize membrane reformation that occurs when these amphiphiles are placed in contact with supported lipid bilayers (SLBs) composed of (i) 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) containing varying amounts of cholesterol or (ii) mixtures of DOPC and either 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE, a conical zwitterionic lipid) or 1,2-dioleoyl-sn-glycero-3-phospho-l-serine (DOPS, a model anionic lipid). In general, we observe these mixed-lipid membranes to undergo remodeling events, including the formation and subsequent collapse of long tubules and the formation of hemispherical caps, upon introduction to biologically relevant concentrations of 3-oxo-C12-AHL and 3-oxo-C12-HS in ways that differ substantially from those observed in single-component DOPC membranes. These differences in bilayer reformation and their associated dynamics can be understood in terms of the influence of membrane composition on the time scales of molecular flip-flop, lipid packing defects, and lipid phase segregation in these materials. The lipid components investigated here are representative of classes of lipids that comprise both naturally occurring cell membranes and many useful synthetic soft materials. These studies thus represent a first step toward understanding the ways in which membrane composition can impact interactions with this important class of bacterial signaling molecules.

Medium-Chain Lipid Conjugation Facilitates Cell-Permeability and Bioactivity.

The majority of bioactive molecules act on membrane proteins or intracellular targets and therefore needs to partition into or cross biological membranes. Natural products often exhibit lipid modifications to facilitate critical molecule-membrane interactions, and in many cases their bioactivity is markedly reduced upon removal of a lipid group. However, despite its importance in nature, lipid-conjugation of small molecules is not commonly used in chemical biology and medicinal chemistry, and the effect of such conjugation has not been systematically studied. To understand the composition of lipids found in natural products, we carried out a chemoinformatic characterization of the "natural product lipidome". According to this analysis, lipidated natural products predominantly contain saturated medium-chain lipids (MCLs), which are significantly shorter than the long-chain lipids (LCLs) found in membranes and lipidated proteins. To study the usefulness of such modifications in probe design, we systematically explored the effect of lipid conjugation on five different small molecule chemotypes and find that permeability, cellular retention, subcellular localization, and bioactivity can be significantly modulated depending on the type of lipid tail used. We demonstrate that MCL conjugation can render molecules cell-permeable and modulate their bioactivity. With all explored chemotypes, MCL-conjugates consistently exhibited superior uptake or bioactivity compared to LCL-conjugates and either comparable or superior uptake or bioactivity to short-chain lipid (SCL)-conjugates. Together, our findings suggest that conjugation of small molecules with MCLs could be a powerful strategy for the design of probes and drugs.

Ordering Transitions of Liquid Crystals Triggered by Metal Oxide-catalyzed Reactions of Sulfur Oxide Species.

Liquid crystals (LCs), when supported on reactive surfaces, undergo changes in ordering that can propagate over distances of micrometers, thus providing a general and facile mechanism to amplify atomic-scale transformations on surfaces into the optical scale. While reactions on organic and metal substrates have been coupled to LC-ordering transitions, metal oxide substrates, which offer unique catalytic activities for reactions involving atmospherically important chemical species such as oxidized sulfur species, have not been explored. Here, we investigate this opportunity by designing LCs that contain 4'-cyanobiphenyl-4-carboxylic acid (CBCA) and respond to surface reactions triggered by parts-per-billion concentrations of SO2 gas on anatase (101) substrates. We used electronic structure calculations to predict that the carboxylic acid group of CBCA binds strongly to anatase (101) in a perpendicular orientation, a prediction that we validated in experiments in which CBCA (0.005 mol %) was doped into an LC (4'-n-pentyl-4-biphenylcarbonitrile). Both experiment and computational modeling further demonstrated that SO3-like species, produced by a surface-catalyzed reaction of SO2 with H2O on anatase (101), displace CBCA from the anatase surface, resulting in an orientational transition of the LC. Experiments also reveal the LC response to be highly selective to SO2 over other atmospheric chemical species (including H2O, NH3, H2S, and NO2), in agreement with our computational predictions for anatase (101) surfaces. Overall, we establish that the catalytic activities of metal oxide surfaces offer the basis of a new class of substrates that trigger LCs to undergo ordering transitions in response to chemical species of relevance to atmospheric chemistry.

A simple simulation-derived descriptor for the deposition of polymer-wrapped carbon nanotubes on functionalized substrates.

Controlling the deposition of polymer-wrapped single-walled carbon nanotubes (s-CNTs) onto functionalized substrates can enable the fabrication of s-CNT arrays for semiconductor devices. In this work, we utilize classical atomistic molecular dynamics (MD) simulations to show that a simple descriptor of solvent structure near silica substrates functionalized by a wide variety of self-assembled monolayers (SAMs) can predict trends in the deposition of s-CNTs from toluene. Free energy calculations and experiments indicate that those SAMs that lead to maximum disruption of solvent structure promote deposition to the greatest extent. These findings are consistent with deposition being driven by solvent-mediated interactions that arise from SAM-solvent interactions, rather than direct s-CNT-SAM interactions, and will permit the rapid computational exploration of potential substrate designs for controlling s-CNT deposition and alignment.

Identifying nonadditive contributions to the hydrophobicity of chemically heterogeneous surfaces via dual-loop active learning.

Hydrophobic interactions drive numerous biological and synthetic processes. The materials used in these processes often possess chemically heterogeneous surfaces that are characterized by diverse chemical groups positioned in close proximity at the nanoscale; examples include functionalized nanomaterials and biomolecules, such as proteins and peptides. Nonadditive contributions to the hydrophobicity of such surfaces depend on the chemical identities and spatial patterns of polar and nonpolar groups in ways that remain poorly understood. Here, we develop a dual-loop active learning framework that combines a fast reduced-accuracy method (a convolutional neural network) with a slow higher-accuracy method (molecular dynamics simulations with enhanced sampling) to efficiently predict the hydration free energy, a thermodynamic descriptor of hydrophobicity, for nearly 200 000 chemically heterogeneous self-assembled monolayers (SAMs). Analysis of this dataset reveals that SAMs with distinct polar groups exhibit substantial variations in hydrophobicity as a function of their composition and patterning, but the clustering of nonpolar groups is a common signature of highly hydrophobic patterns. Further molecular dynamics analysis relates such clustering to the perturbation of interfacial water structure. These results provide new insight into the influence of chemical heterogeneity on hydrophobicity via quantitative analysis of a large set of surfaces, enabled by the active learning approach.

Interactions of Bacterial Quorum Sensing Signals with Model Lipid Membranes: Influence of Acyl Tail Structure on Multiscale Response.

Many common bacteria use amphiphilic N-acyl-L-homoserine lactones (AHLs) as signaling molecules to coordinate group behaviors at high cell densities. Past studies demonstrate that AHLs can adsorb to and promote the remodeling of lipid membranes in ways that could underpin cell-cell or host-cell interactions. Here, we report that changes in AHL acyl tail group length and oxidation state (e.g., the presence or absence of a 3-oxo group) can lead to differences in the interactions of eight naturally occurring AHLs in solution and in contact with model lipid membranes. Our results reveal that the presence of a 3-oxo group impacts remodeling when AHLs are placed in contact with supported lipid bilayers (SLBs) of the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). Whereas AHLs that have 3-oxo groups generally promote the formation of microtubules, AHLs that lack 3-oxo groups generally form hemispherical caps on the surfaces of SLBs. These results are interpreted in terms of the time scales on which AHLs translocate across bilayers to relieve asymmetrical bilayer stress. Quartz crystal microbalance with dissipation measurements also reveal that 3-oxo AHLs associate with DOPC bilayers to a greater extent than their non-3-oxo analogues. In contrast, we observed no monotonic relationship between AHL tail length and bilayer reformation. Finally, we observed that 3-oxo AHLs facilitate greater transport or leakage of molecular cargo across the membranes of DOPC vesicles relative to AHLs without 3-oxo groups, also suggesting increased bilayer disruption and destabilization. These fundamental studies hint at interactions and associated multiscale phenomena that may inform current interpretations of the behaviors of AHLs in biological contexts. These results could also provide guidance useful for the design of new classes of synthetic materials (e.g., sensor elements or drug delivery vehicles) that interact with or respond selectively to communities of bacteria that use 3-oxo AHLs for cell-cell communication.

Bacterial Quorum Sensing Signals Promote Large-Scale Remodeling of Lipid Membranes.

We report that N-acyl-l-homoserine lactones (AHLs), a class of nonionic amphiphiles that common bacteria use as signals to coordinate group behaviors, can promote large-scale remodeling in model lipid membranes. Characterization of supported lipid bilayers (SLBs) of the phospholipid 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC) by fluorescence microscopy and quartz crystal microbalance with dissipation (QCM-D) reveals the well-studied AHL signal 3-oxo-C12-AHL and its anionic head group hydrolysis product (3-oxo-C12-HS) to promote the formation of long microtubules that can retract into hemispherical caps on the surface of the bilayer. These transformations are dynamic, reversible, and dependent upon the head group structure. Additional experiments demonstrate that 3-oxo-C12-AHL can promote remodeling to form microtubules in lipid vesicles and promote molecular transport across bilayers. Molecular dynamics (MD) simulations predict differences in thermodynamic barriers to translocation of these amphiphiles across a bilayer that are reflected in both the type and extent of reformation and associated dynamics. Our experimental observations can thus be interpreted in terms of accumulation and relief of asymmetric stresses in the inner and outer leaflets of a bilayer upon intercalation and translocation of these amphiphiles. Finally, experiments on Pseudomonas aeruginosa, a pathogen that uses 3-oxo-C12-AHL for cell-to-cell signaling, demonstrate that 3-oxo-C12-AHL and 3-oxo-C12-HS can promote membrane remodeling at biologically relevant concentrations and in the absence of other biosurfactants, such as rhamnolipids, that are produced at high population densities. Overall, these results have implications for the roles that 3-oxo-C12-AHL and its hydrolysis product may play in not only mediating intraspecies bacterial communication but also processes such as interspecies signaling and bacterial control of host-cell response. Our findings also provide guidance that could prove useful for the design of synthetic self-assembled materials that respond to bacteria in ways that are useful in the context of sensing, drug delivery, and in other fundamental and applied areas.

Molecular Order Affects Interfacial Water Structure and Temperature-Dependent Hydrophobic Interactions between Nonpolar Self-Assembled Monolayers.

Understanding how material properties affect hydrophobic interactions-the water-mediated interactions that drive the association of nonpolar materials-is vital to the design of materials in contact with water. Conventionally, the magnitude of the hydrophobic interactions between extended interfaces is attributed to interfacial chemical properties, such as the amount of nonpolar solvent-exposed surface area. However, recent experiments have demonstrated that the hydrophobic interactions between uniformly nonpolar self-assembled monolayers (SAMs) also depend on molecular-level SAM order. In this work, we use atomistic molecular dynamics simulations to investigate the relationship between SAM order, water structure, and hydrophobic interactions to explain these experimental observations. The SAM-SAM hydrophobic interactions calculated from the simulations increase in magnitude as SAM order increases, matching experimental observations. We explain this trend by showing that the molecular-level order of the SAM impacts the nanoscale structure of interfacial water molecules, leading to an increase in water structure near disordered SAMs. These findings are consistent with a decrease in the solvation entropy of disordered SAMs, which is confirmed by measuring the temperature dependence of hydrophobic interactions using both simulations and experiments. This study elucidates how hydrophobic interactions can be influenced by an interfacial physical property, which may guide the design of synthetic materials with fine-tuned interfacial hydrophobicity.

Solvent-Mediated Affinity of Polymer-Wrapped Single-Walled Carbon Nanotubes for Chemically Modified Surfaces.

Semiconducting single-walled carbon nanotube (s-CNT) arrays are being explored for next-generation semiconductor electronics. Even with the multitude of alignment and spatially localized s-CNT deposition methods designed to control s-CNT deposition, fundamental understanding of the driving forces for s-CNT deposition is still lacking. The individual roles of the dispersant, solvent, target substrate composition, and the s-CNT itself are not completely understood because it is difficult to decouple deposition parameters. Here, we study poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(6,6'-[2,2'-{bipyridine}])] (PFO-BPy)-wrapped s-CNT deposition from solution onto a chemically modified substrate. We fabricate various self-assembled monolayers (SAMs) to gain a greater understanding of substrate effects on PFO-BPy-wrapped s-CNT deposition. We observe that s-CNT deposition is dependent on both the target substrate and s-CNT dispersion solvent. To complement the experiments, molecular dynamics simulations of PFO-BPy-wrapped s-CNT deposition on two different SAMs are performed to obtain mechanistic insights into the effect of the substrate and solvent on s-CNT deposition. We find that the global free-energy minimum associated with favorable s-CNT adsorption occurs for a configuration in which the minimum of the solvent density around the s-CNT coincides with the minimum of the solvent density above a SAM-grafted surface, indicating that solvent structure near a SAM-grafted surface determines the adsorption free-energy landscape driving s-CNT deposition. Our results will help guide informative substrate design for s-CNT array fabrication in semiconductor devices.

Structure-Property Relationships of Amphiphilic Nanoparticles That Penetrate or Fuse Lipid Membranes.

The development of synthetic nanomaterials that could embed within, penetrate, or induce fusion between membranes without permanent disruption would have great significance for biomedical applications. Here we describe structure-function relationships of highly water-soluble gold nanoparticles comprised of an ∼1.5-5 nm diameter metal core coated by an amphiphilic organic ligand shell, which exhibit membrane embedding and fusion activity mediated by the surface ligands. Using an environment-sensitive dye anchored within the ligand shell as a sensor of membrane embedding, we demonstrate that particles with core sizes of ∼2-3 nm are capable of embedding within and penetrating fluid bilayers. At the nanoscale, these particles also promote spontaneous fusion of liposomes or spontaneously embed within intact liposomal vesicles. These studies provide nanoparticle design and selection principles that could be used in drug delivery applications, as membrane stains, or for the creation of novel organic/inorganic nanomaterial self-assemblies.

Structurally detailed coarse-grained model for Sec-facilitated co-translational protein translocation and membrane integration.

We present a coarse-grained simulation model that is capable of simulating the minute-timescale dynamics of protein translocation and membrane integration via the Sec translocon, while retaining sufficient chemical and structural detail to capture many of the sequence-specific interactions that drive these processes. The model includes accurate geometric representations of the ribosome and Sec translocon, obtained directly from experimental structures, and interactions parameterized from nearly 200 µs of residue-based coarse-grained molecular dynamics simulations. A protocol for mapping amino-acid sequences to coarse-grained beads enables the direct simulation of trajectories for the co-translational insertion of arbitrary polypeptide sequences into the Sec translocon. The model reproduces experimentally observed features of membrane protein integration, including the efficiency with which polypeptide domains integrate into the membrane, the variation in integration efficiency upon single amino-acid mutations, and the orientation of transmembrane domains. The central advantage of the model is that it connects sequence-level protein features to biological observables and timescales, enabling direct simulation for the mechanistic analysis of co-translational integration and for the engineering of membrane proteins with enhanced membrane integration efficiency.

Solvent-exposed lipid tail protrusions depend on lipid membrane composition and curvature.

The stochastic protrusion of hydrophobic lipid tails into solution, a subclass of hydrophobic membrane defects, has recently been shown to be a critical step in a number of biological processes like membrane fusion. Understanding the factors that govern the appearance of lipid tail protrusions is critical for identifying membrane features that affect the rate of fusion or other processes that depend on contact with solvent-exposed lipid tails. In this work, we utilize atomistic molecular dynamics simulations to characterize the likelihood of tail protrusions in phosphotidylcholine lipid bilayers of varying composition, curvature, and hydration. We distinguish two protrusion modes corresponding to atoms near the end of the lipid tail or near the glycerol group. Through potential of mean force calculations, we demonstrate that the thermodynamic cost for inducing a protrusion depends on tail saturation but is insensitive to other bilayer structural properties or hydration above a threshold value. Similarly, highly curved vesicles or micelles increase both the overall frequency of lipid tail protrusions as well as the preference for splay protrusions, both of which play an important role in driving membrane fusion. In multi-component bilayers, however, the incidence of protrusion events does not clearly depend on the mismatch between tail length or tail saturation of the constituent lipids. Together, these results provide significant physical insight into how system components might affect the appearance of protrusions in biological membranes, and help explain the roles of composition or curvature-modifying proteins in membrane fusion.

Influence of Order within Nonpolar Monolayers on Hydrophobic Interactions.

We report an experimental investigation of the influence of molecular-level order (crystallinity) within nonpolar monolayers on hydrophobic interactions. The measurements were performed using gold film-supported monolayers formed from alkanethiols (CH3(CH2)nSH, with n ranging from 3 to 17), which we confirmed by using polarization-modulation infrared reflection-adsorption spectroscopy to exhibit chain-length-dependent order (methylene peak moves from 2926 to 2919 cm-1, corresponding to a transition from liquid- to quasi-crystalline-like order) in the absence of substantial changes in chain density (constant methyl peak intensity). By using monolayer-covered surfaces immersed in either aqueous triethanolamine (TEA, 10 mM, pH 7.0) or pure methanol, we quantified hydrophobic and van der Waals contributions to adhesive interactions between identical pairs of surfaces (measured using an atomic force microscope) as a function of the length and order of the aliphatic chains within the monolayers. In particular, we measured pull-off forces arising from hydrophobic adhesion to increase in a nonlinear manner with chain length (abrupt increase between n = 5 and 6 from 2.1 ± 0.3 to 14.1 ± 0.7 nN) and to correlate closely with a transition from a liquid-like to crystalline-like monolayer phase. In contrast, adhesion in methanol increased gradually with chain length from 0.3 ± 0.1 to 3.2 ± 0.3 nN for n = 3 to 7 and then did not change further with an increase in chain length. These results lead to the hypothesis that order within nonpolar monolayers influences hydrophobic interactions. Additional support for this hypothesis was obtained from measurements reported in this paper using long-chain alkanethiols (ordered) and alkenethiols (disordered). The results are placed into the context of recent spectroscopic studies of hydrogen bonding of water at nonpolar monolayers. Overall, our study provides new insight into factors that influence hydrophobic interactions at nonpolar monolayers.

Pathway for insertion of amphiphilic nanoparticles into defect-free lipid bilayers from atomistic molecular dynamics simulations.

Gold nanoparticles (NPs) have been increasingly used in biological applications that involve potential contact with cellular membranes. As a result, it is essential to gain a physical understanding of NP-membrane interactions to guide the design of next-generation bioactive nanoparticles. In previous work, we showed that charged, amphiphilic NPs can fuse with lipid bilayers after contact between protruding solvent-exposed lipid tails and the NP monolayer. Fusion was only observed at the high-curvature edges of large bilayer defects, but not in low-curvature regions where protrusions are rarely observed. Here, we use atomistic molecular dynamics simulations to show that the same NPs can also fuse with low-curvature bilayers in the absence of defects if NP-protrusion contact occurs, generalizing the results of our previous work. Insertion proceeds without applying biasing forces to the NP, driven by the hydrophobic effect, and involves the transient generation of bilayer curvature. We further find that NPs with long hydrophobic ligands can insert a single ligand into the bilayer core in a manner similar to the binding of peripheral proteins. Such anchoring may precede insertion, revealing potential methods for engineering NP monolayers to enhance NP-bilayer fusion in systems with a low likelihood of lipid tail protrusions. These results reveal new pathways for NP-bilayer fusion and provide fundamental insight into behavior at the nano-bio interface.

Free energy change for insertion of charged, monolayer-protected nanoparticles into lipid bilayers.

Charged, monolayer-protected gold nanoparticles (AuNPs) with core diameters smaller than 10 nm have recently emerged as a prominent class of nanomaterial for use in targeted drug delivery and biosensing. In particular, recent experimental studies showed that AuNPs protected by a binary mixture of purely hydrophobic and anionic, end-functionalized alkanethiol ligands were able to spontaneously penetrate through cell membranes via a non-endocytic, non-disruptive mechanism. The critical step in the penetration process is a fusion step during which the AuNPs insert into the hydrophobic core of the bilayer. This fusion step is driven by hydrophobic forces as inserted AuNPs minimize their exposed hydrophobic surface area and thereby lower their free energy compared to particles in the bulk. Here, we explore the effect of the large parameter space of composition, size, ligand length, morphology, and hydrophobicity strength on the change in the free energy upon insertion. Using a newly developed implicit bilayer, implicit solvent simulation model, our work shows that there is a size cutoff for insertion that has a strong dependence on surface composition and ligand chemistry. Our results agree well with previous experimental findings for a particular value of the hydrophobicity strength. This work provides physical insight that may be used to both understand the insertion of AuNPs into bilayers and guide the design of monolayers to either encourage or inhibit insertion.

Fusion of ligand-coated nanoparticles with lipid bilayers: effect of ligand flexibility.

Amphiphilic, monolayer-protected gold nanoparticles (AuNPs) have recently been shown to insert into and fuse with lipid bilayers, driven by the hydrophobic effect. The inserted transmembrane state is stabilized by the "snorkeling" of charged ligand end groups out of the bilayer interior. This snorkeling process is facilitated by the backbone flexibility of the alkanethiol ligands that comprise the monolayer. In this work, we show that fusion is favorable even in the absence of backbone flexibility by modeling the ligands as rigid rods. For rigid ligands, snorkeling is still accommodated by rotations of the ligand with respect to the grafting point, but the process incurs a more significant free energy penalty than if the backbone were fully flexible. We show that the rigid rod model predicts similar trends in the free energy change for insertion as the previous flexible model when the size of the AuNPs is varied. However, the rigidity of the ligand backbone reduces the overall magnitude of the free energy change compared to that of the flexible model. These results thus generalize previous findings to systems with hindered backbone flexibility due to either structural constraints or low temperature.

Effect of particle diameter and surface composition on the spontaneous fusion of monolayer-protected gold nanoparticles with lipid bilayers.

Anionic, monolayer-protected gold nanoparticles (AuNPs) have been shown to nondisruptively penetrate cellular membranes. Here, we show that a critical first step in the penetration process is potentially the fusion of such AuNPs with lipid bilayers. Free energy calculations, experiments on unilamellar and multilamellar vesicles, and cell studies all support this hypothesis. Furthermore, we show that fusion is only favorable for AuNPs with core diameters below a critical size that depends on the monolayer composition.

Ligand Lipophilicity Determines Molecular Mechanisms of Nanoparticle Adsorption to Lipid Bilayers.

The interactions of ligand-functionalized nanoparticles with the cell membrane affect cellular uptake, cytotoxicity, and related behaviors, but relating these interactions to ligand properties remains challenging. In this work, we perform coarse-grained molecular dynamics simulations to study how the adsorption of ligand-functionalized cationic gold nanoparticles (NPs) to a single-component lipid bilayer (as a model cell membrane) is influenced by ligand end group lipophilicity. A set of 2 nm diameter NPs, each coated with a monolayer of organic ligands that differ only in their end groups, was simulated to mimic NPs recently studied experimentally. Metadynamics calculations were performed to determine key features of the free energy landscape for adsorption as a function of the distance of the NP from the bilayer and the number of NP-lipid contacts. These simulations revealed that NP adsorption is thermodynamically favorable for all NPs due to the extraction of lipids from the bilayer and into the NP monolayer. To resolve ligand-dependent differences in adsorption behavior, string method calculations were performed to compute minimum free energy pathways for adsorption. These calculations revealed a surprising nonmonotonic dependence of the free energy barrier for adsorption on ligand end group lipophilicity. Large free energy barriers are predicted for the least lipophilic end groups because favorable NP-lipid contacts are initiated only through the unfavorable protrusion of lipid tail groups out of the bilayer. The smallest free energy barriers are predicted for end groups of intermediate lipophilicity which promote NP-lipid contacts by intercalating within the bilayer. Unexpectedly, large free energy barriers are also predicted for the most lipophilic end groups which remain sequestered within the ligand monolayer rather than intercalating within the bilayer. These trends are broadly in agreement with past experimental measurements and reveal how subtle variations in ligand lipophilicity dictate adsorption mechanisms and associated kinetics by influencing the interplay of lipid-ligand interactions.

Nanocrystal Assemblies: Current Advances and Open Problems.

We explore the potential of nanocrystals (a term used equivalently to nanoparticles) as building blocks for nanomaterials, and the current advances and open challenges for fundamental science developments and applications. Nanocrystal assemblies are inherently multiscale, and the generation of revolutionary material properties requires a precise understanding of the relationship between structure and function, the former being determined by classical effects and the latter often by quantum effects. With an emphasis on theory and computation, we discuss challenges that hamper current assembly strategies and to what extent nanocrystal assemblies represent thermodynamic equilibrium or kinetically trapped metastable states. We also examine dynamic effects and optimization of assembly protocols. Finally, we discuss promising material functions and examples of their realization with nanocrystal assemblies.