Tiffany R. Walsh

Archetypal energy landscapes

Energy landscapes hold the key to understanding a wide range of molecular phenomena. The problem of how a denatured protein re-folds to its active state (Levinthals parado) has been addressed in terms of the underlying energy landscape, as has the widely used ‘strong’ and ‘fragile’ classification of liquids,. Here we show how three archetypal energy landscapes for clusters of atoms or molecules can be characterized in terms of the disconnectivity graphs of their energy minima—that is, in terms of the pathways that connect minima at different threshold energies. First we consider a cluster of 38 Lennard–Jones particles, whose energy landscape is a ‘double funnel’ on which relaxation to the global minimum is diverted into a set of competing structures. Then we characterize the energy landscape associated with the annealing of C60 cages to buckministerfullerene, and show that it provides experimentally accessible clues to the relaxation pathway. Finally we show a very different landscape morphology, that of a model water cluster (H2O)20, and show how it exhibits features expected for a ‘strong’ liquid. These three examples do not exhaust the possibilities, and might constitute substructures of still more complex landscapes.

GolP-CHARMM: First-principles based force fields for the interaction of proteins with Au(111) and Au(100)

Computational simulation of peptide adsorption at the aqueous gold interface is key to advancing the development of many applications based on gold nanoparticles, ranging from nanomedical devices to smart biomimetic materials. Here, we present a force field, GolP-CHARMM, designed to capture peptide adsorption at both the aqueous Au(111) and Au(100) interfaces. The force field, compatible with the bio-organic force field CHARMM, is parametrized using a combination of experimental and first-principles data. Like its predecessor, GolP (Iori, F.; et al. J. Comput. Chem.2009, 30, 1465), this force field contains terms to describe the dynamic polarization of gold atoms, chemisorbing species, and the interaction between sp(2) hybridized carbon atoms and gold. A systematic study of small molecule adsorption at both surfaces using the vdW-DF functional (Dion, M.; et al. Phys. Rev. Lett.2004, 92, 246401-1. Thonhauser, T.; et al. Phys. Rev. B2007, 76, 125112) is carried out to fit and test force field parameters and also, for the first time, gives unique insights into facet selectivity of gold binding in vacuo. Energetic and spatial trends observed in our DFT calculations are reproduced by the force field under the same conditions. Finally, we use the new force field to calculate adsorption energies, under aqueous conditions, for a representative set of amino acids. These data are found to agree with experimental findings.

Interplay of sequence, conformation, and binding at the Peptide-titania interface as mediated by water.

The initial stages of the adsorption of a hexapeptide at the aqueous titania interface are modeled using atomistic molecular dynamics simulations. This hexapeptide has been identified by experiment [Sano, K. I.; Shiba, K. J. Am. Chem. Soc. 2003, 125, 14234] to bind to Ti particles. We explore the current hypothesis presented by these authors that binding at this peptide-titania interface is the result of electrostatic interactions and find that contact with the surface appears to take place via a pair of oppositely charged groups in the peptide. Our data indicate that the peptide may initially recognize the water layers at the interface, not the titania surface itself, via these charged groups. We also report results of simulations for hexapeptide sequences with selected single-point mutations for alanine and compare these behaviors with those suggested from observed binding affinities from existing alanine scan experiments. Our results indicate that factors in addition to electrostatics also contribute, with the structural rigidity conferred by proline suggested to play a significant role. Finally, our findings suggest that intrapeptide interaction may provide mechanisms for surface detachment that could be detrimental to binding at the interface.

Theoretical study of the water pentamer

Geometry optimizations, rearrangement mechanisms, spectral intensities, and tunneling splittings are reported for the water pentamer. Two low energy degenerate rearrangements are identified for the chiral cyclic global minimum which are analogous to processes that lead to observable tunneling splittings in the water trimer. Fourteen different pathways are characterized by ab initio calculations employing basis sets up to double‐zeta plus polarization (DZP) quality with subsequent reoptimization of the associated minima using the Becke exchange and the Lee–Yang–Parr correlation functionals (BLYP) with the same basis. All the pathways have been recomputed for a number of different empirical potentials, some of which reproduce the two lowest energy degenerate rearrangements quite well. However, none of the empirical potentials support all the higher energy ab initio minima. Qualitative estimates of the two tunneling splittings associated with the lowest energy pathways suggest that at least one might be obse...

Biomolecular Recognition Principles for Bionanocombinatorics: An Integrated Approach To Elucidate Enthalpic and Entropic Factors

Bionanocombinatorics is an emerging field that aims to use combinations of positionally encoded biomolecules and nanostructures to create materials and devices with unique properties or functions. The full potential of this new paradigm could be accessed by exploiting specific noncovalent interactions between diverse palettes of biomolecules and inorganic nanostructures. Advancement of this paradigm requires peptide sequences with desired binding characteristics that can be rationally designed, based upon fundamental, molecular-level understanding of biomolecule-inorganic nanoparticle interactions. Here, we introduce an integrated method for building this understanding using experimental measurements and advanced molecular simulation of the binding of peptide sequences to gold surfaces. From this integrated approach, the importance of entropically driven binding is quantitatively demonstrated, and the first design rules for creating both enthalpically and entropically driven nanomaterial-binding peptide sequences are developed. The approach presented here for gold is now being expanded in our laboratories to a range of inorganic nanomaterials and represents a key step toward establishing a bionanocombinatorics assembly paradigm based on noncovalent peptide-materials recognition.

Hydrolysis of the amorphous silica surface. II. Calculation of activation barriers and mechanisms

Using a previously derived model of the dry, amorphous, hydrophilic SiO2 surface, the reactivity of generic defect sites on the surface with respect to water, and the local network rearrangement that accompanies hydrolysis at these sites, is investigated using cluster models. Ab initio methods are used to calculate reaction barriers and reaction pathways. Consequences of the various types of hydrolysis product found are discussed with reference to potential sites for polymer chemisorption on the hydrolyzed, amorphous SiO2 surface.

Probing the molecular mechanisms of quartz-binding peptides.

Understanding the mechanisms of biomineralization and the realization of biology-inspired inorganic materials formation largely depends on our ability to manipulate peptide/solid interfacial interactions. Material interfaces and biointerfaces are critical sites for bioinorganic synthesis, surface diffusion, and molecular recognition. Recently adapted biocombinatorial techniques permit the isolation of peptides recognizing inorganic solids that are used as molecular building blocks, for example, as synthesizers, linkers, and assemblers. Despite their ubiquitous utility in nanotechnology, biotechnology, and medicine, the fundamental mechanisms of molecular recognition of engineered peptides binding to inorganic surfaces remain largely unknown. To explore propensity rules connecting sequence, structure, and function that play key roles in peptide/solid interactions, we combine two different approaches: a statistical analysis that searches for highly enriched motifs among de novo designed peptides, and, atomistic simulations of three experimentally validated peptides. The two strong and one weak quartz-binding peptides were chosen for the simulations at the quartz (100) surface under aqueous conditions. Solution-based peptide structures were analyzed by circular dichroism measurements. Small and hydrophobic residues, such as Pro, play a key role at the interface by making close contact with the solid and hindering formation of intrapeptide hydrogen bonds. The high binding affinity of a peptide may be driven by a combination of favorable enthalpic and entropic effects, that is, a strong binder may possess a large number of possible binding configurations, many of which having relatively high binding energies. The results signify the role of the local molecular environment among the critical residues that participate in solid binding. The work herein describes molecular conformations inherent in material-specific peptides and provides fundamental insight into the atomistic understanding of peptide/solid interfaces.

Atomistic modelling of the interaction between peptides and carbon nanotubes

Interactions between single-walled carbon nanotubes (SWNT) and peptides are investigated. An existing polarizable force field, using distributed multipoles up to quadrupoles for the electrostatics, is modified to include a description of the non-bonded interactions between a SWNT and peptides. Adsorption energies and structures calculated with this potential are compared with data from electronic structure theory. Simulations of binding and non-binding peptide aptamers, as identified from experiment, are shown to agree with current experimental observations.

Theoretical study of the water tetramer

We report rearrangement mechanisms and new stationary points for the water tetramer and deduce the associated tunneling splitting patterns and nuclear spin weights when different processes are assumed to be feasible. The basis sets employed for the ab initio calculations are double-zeta plus polarization (DZP) and DZP with additional diffuse functions (DZP+diff), and results have been obtained within both the Hartree–Fock (HF) and density functional theory frameworks employing the Becke exchange and the Lee–Yang–Parr correlation functionals (BLYP). The results are compared with those found for a relatively sophisticated empirical rigid-body intermolecular potential. One direct degenerate rearrangement of the cyclic global minimum was characterized in the HF calculations, but disappears when density functional theory is applied. The latter mechanism involves a larger barrier than pathways mediated by higher index saddle points belonging to the torsional space. In principle, doublet splittings could result ...

Efficient conformational sampling of peptides adsorbed onto inorganic surfaces: insights from a quartz binding peptide

Harnessing the properties of biomolecules, such as peptides, adsorbed on inorganic surfaces is of interest to many cross-disciplinary areas of science, ranging from biomineralisation to nanomedicine. Key to advancing research in this area is determination of the peptide conformation(s) in its adsorbed state, at the aqueous interface. Molecular simulation is one such approach for accomplishing this goal. In this respect, use of temperature-based replica-exchange molecular dynamics (T-REMD) can yield enhanced sampling of the interfacial conformations, but does so at great computational expense, chiefly because of the need to include an explicit representation of water at the interface. Here, we investigate a number of more economical variations on REMD, chiefly those based on Replica Exchange with Solvent Tempering (REST), using the aqueous quartz-binding peptide S1-(100) α-quartz interfacial system as a benchmark. We also incorporate additional implementation details specifically targeted at improving sampling of biomolecules at interfaces. We find the REST-based variants yield configurational sampling of the peptide-surface system comparable with T-REMD, at a fraction of the computational time and resource. Our findings also deliver novel insights into the binding behaviour of the S1 peptide at the quartz (100) surface that are consistent with available experimental data.