Free energy of metal-organic framework self-assembly.

Metal-organic frameworks (MOFs) represent an important class of materials. Careful selection of building blocks allows for tailoring of the properties of the resulting framework. The self-assembly process, however, is not understood, and without detailed knowledge of the underlying molecular mechanism, it is difficult to anticipate whether a particular design can be realized, or whether the material adopts a metastable, kinetically arrested state. We present a detailed examination of early-stage self-assembly pathways of the MOF-5. Enhanced sampling techniques are used to model a self-assembly in an explicit solvent (dimethylformamide, DMF). We identify several free energy barriers encountered during the assembly of the final MOF, which arise from structural rearrangements preceding MOF formation and from disrupted MOF-solvent interactions as formation proceeds. In all cases considered here, MOFs exhibit favorable entropic gains during the assembly. More generally, the strategy presented provides a step toward the experimental design characterizing the formation of ordered frameworks and possible sources of polymorphism.

Defining the Structure of a Protein-Spherical Nucleic Acid Conjugate and Its Counterionic Cloud.

Protein-spherical nucleic acid conjugates (Pro-SNAs) are an emerging class of bioconjugates that have properties defined by their protein cores and dense shell of oligonucleotides. They have been used as building blocks in DNA-driven crystal engineering strategies and show promise as agents that can cross cell membranes and affect both protein and DNA-mediated processes inside cells. However, ionic environments surrounding proteins can influence their activity and conformational stability, and functionalizing proteins with DNA substantively changes the surrounding ionic environment in a nonuniform manner. Techniques typically used to determine protein structure fail to capture such irregular ionic distributions. Here, we determine the counterion radial distribution profile surrounding Pro-SNAs dispersed in RbCl with 1 nm resolution through in situ anomalous small-angle X-ray scattering (ASAXS) and classical density functional theory (DFT). SAXS analysis also reveals the radial extension of the DNA and the linker used to covalently attach the DNA to the protein surface. At the experimental salt concentration of 50 mM RbCl, Rb+ cations compensate ∼90% of the negative charge due to the DNA and linker. Above 75 mM, DFT calculations predict overcompensation of the DNA charge by Rb+. This study suggests a method for exploring Pro-SNA structure and function in different environments through predictions of ionic cloud densities as a function of salt concentration, DNA grafting density, and length. Overall, our study demonstrates that solution X-ray scattering combined with DFT can discern counterionic distribution and submolecular features of highly charged, complex nanoparticle constructs such as Pro-SNAs and related nucleic acid conjugate materials.

Membrane Permeation versus Amyloidogenicity: A Multitechnique Study of Islet Amyloid Polypeptide Interaction with Model Membranes.

Islet amyloid polypeptide (IAPP) is responsible for cell depletion in the pancreatic islets of Langherans, and for multiple pathological consequences encountered by patients suffering from type 2 Diabetes Mellitus. We have examined the amyloidogenicity and cytotoxic mechanisms of this peptide by investigating model-membrane permeation and structural effects of fragments of the human IAPP and several rat IAPP mutants. In vitro experiments and molecular dynamics simulations reveal distinct physical segregation, membrane permeation, and amyloid aggregation processes that are mediated by two separate regions of the peptide. These observations suggest a "detergent-like" mechanism, where lipids are extracted from the bilayer by the N-terminus of IAPP, and integrated into amyloid aggregates. The amyloidogenic aggregation would kinetically compete with the process of membrane permeation and, therefore, inhibit it. This hypothesis represents a new perspective on the mechanism underlying the membrane disruption by amyloid peptides, and could influence the development of new therapeutic strategies.

Secondary Structure of Rat and Human Amylin across Force Fields.

The aggregation of human amylin has been strongly implicated in the progression of Type II diabetes. This 37-residue peptide forms a variety of secondary structures, including random coils, α-helices, and ß-hairpins. The balance between these structures depends on the chemical environment, making amylin an ideal candidate to examine inherent biases in force fields. Rat amylin differs from human amylin by only 6 residues; however, it does not form fibrils. Therefore it provides a useful complement to human amylin in studies of the key events along the aggregation pathway. In this work, the free energy of rat and human amylin was determined as a function of α-helix and ß-hairpin content for the Gromos96 53a6, OPLS-AA/L, CHARMM22/CMAP, CHARMM22*, Amberff99sb*-ILDN, and Amberff03w force fields using advanced sampling techniques, specifically bias exchange metadynamics. This work represents a first systematic attempt to evaluate the conformations and the corresponding free energy of a large, clinically relevant disordered peptide in solution across force fields. The NMR chemical shifts of rIAPP were calculated for each of the force fields using their respective free energy maps, allowing us to quantitatively assess their predictions. We show that the predicted distribution of secondary structures is sensitive to the choice of force-field: Gromos53a6 is biased towards ß-hairpins, while CHARMM22/CMAP predicts structures that are overly α-helical. OPLS-AA/L favors disordered structures. Amberff99sb*-ILDN, AmberFF03w and CHARMM22* provide the balance between secondary structures that is most consistent with available experimental data. In contrast to previous reports, our findings suggest that the equilibrium conformations of human and rat amylin are remarkably similar, but that subtle differences arise in transient alpha-helical and beta-strand containing structures that the human peptide can more readily adopt. We hypothesize that these transient states enable dynamic pathways that facilitate the formation of aggregates and, eventually, amyloid fibrils.

Chirality-selected phase behaviour in ionic polypeptide complexes.

Polyelectrolyte complexes present new opportunities for self-assembled soft matter. Factors determining whether the phase of the complex is solid or liquid remain unclear. Ionic polypeptides enable examination of the effects of stereochemistry on complex formation. Here we demonstrate that chirality determines the state of polyelectrolyte complexes, formed from mixing dilute solutions of oppositely charged polypeptides, via a combination of electrostatic and hydrogen-bonding interactions. Fluid complexes occur when at least one of the polypeptides in the mixture is racemic, which disrupts backbone hydrogen-bonding networks. Pairs of purely chiral polypeptides, of any sense, form compact, fibrillar solids with a ß-sheet structure. Analogous behaviour occurs in micelles formed from polypeptide block copolymers with polyethylene oxide, where assembly into aggregates with either solid or fluid cores, and eventually into ordered phases at high concentrations, is possible. Chirality is an exploitable tool for manipulating material properties in polyelectrolyte complexation.

Interfacial Tension of Polyelectrolyte Complex Coacervate Phases.

We consider polyelectrolyte solutions which, under suitable conditions, phase separate into a liquid-like coacervate phase and a coexisting supernatant phase that exhibit an extremely low interfacial tension. Such interfacial tension provides the basis for most coacervate-based applications, but little is known about it, including its dependence on molecular weight, charge density, and salt concentration. By combining a Debye-Hückel treatment for electrostatic interactions with the Cahn-Hilliard theory, we derive explicit expressions for this interfacial tension. In the absence of added salts, we find that the interfacial tension scales as N-3/2(η/ηc-1)3/2 near the critical point of the demixing transition, and that it scales as η1/2 far away from it, where N is the chain length and η measures the electrostatic interaction strength as a function of temperature, dielectric constant, and charge density of the polyelectrolytes. For the case with added salts, we find that the interfacial tension scales with the salt concentration ψ as N-1/4(1-ψ/ψc)3/2 near the critical salt concentration ψc. Our predictions are shown to be in quantitative agreement with experiments and provide a means to design new materials based on polyelectrolyte complexation.