Interaction of β-Sheet Folds with a Gold Surface

The adsorption of proteins on inorganic surfaces is of fundamental biological importance. Further, biomedical and nanotechnological applications increasingly use interfaces between inorganic material and polypeptides. Yet, the underlying adsorption mechanism of polypeptides on surfaces is not well understood and experimentally difficult to analyze. Therefore, we investigate here the interactions of polypeptides with a gold(111) surface using computational molecular dynamics (MD) simulations with a polarizable gold model in explicit water. Our focus in this paper is the investigation of the interaction of polypeptides with β-sheet folds. First, we concentrate on a β-sheet forming model peptide. Second, we investigate the interactions of two domains with high β-sheet content of the biologically important extracellular matrix protein fibronectin (FN). We find that adsorption occurs in a stepwise mechanism both for the model peptide and the protein. The positively charged amino acid Arg facilitates the initial contact formation between protein and gold surface. Our results suggest that an effective gold-binding surface patch is overall uncharged, but contains Arg for contact initiation. The polypeptides do not unfold on the gold surface within the simulation time. However, for the two FN domains, the relative domain-domain orientation changes. The observation of a very fast and strong adsorption indicates that in a biological matrix, no bare gold surfaces will be present. Hence, the bioactivity of gold surfaces (like bare gold nanoparticles) will critically depend on the history of particle administration and the proteins present during initial contact between gold and biological material. Further, gold particles may act as seeds for protein aggregation. Structural re-organization and protein aggregation are potentially of immunological importance

A complete quantum mechanical study of chlorine photodissociation.

A fully quantum mechanical dynamical calculation on the photodissociation of molecular chlorine is presented. The magnitudes and phases of all the relevant photofragment T-matrices have been calculated, making this study the computational equivalent of a "complete experiment," where all the possible parameters defining an experiment have been determined. The results are used to simulate cross-sections and angular momentum polarization information which may be compared with experimental data. The calculations rigorously confirm the currently accepted mechanism for the UV photodissociation of Cl(2), in which the majority of the products exit on the C(1)Π(1u) state, with non-adiabatic couplings to the A(3)Π(1u) and several other Ω = 1 states, and a small contribution from the B(3)Π state present at longer wavelengths

The vibrationally mediated photodissociation of Cl2.

The photodissociation of vibrationally excited Cl(2)(v = 1) has been investigated experimentally using the velocity mapped ion imaging technique. The experimental measurements presented here are compared with the results of time-dependent wavepacket calculations performed on a set of ab initio potential energy curves. The high level calculations allow prediction of all the dynamical information regarding the dissociation, including electronic polarization effects. Using a combination of theory and experiment it was found that there was negligible cooling of the vibrational degree of freedom of the parent molecule in the molecular beam. The results presented are compared with those following the photodissociation of Cl(2)(v = 0). Although the same electronic states are found to be important for Cl(2)(v = 1) as for Cl(2)(v = 0), significant differences were found regarding many of the observables. The overall level of agreement between theory and experiment was found to be reasonable and confirms previous assignments of the photodissociation mechanism

Electronic polarization effects in the photodissociation of Cl2.

Velocity mapped ion imaging and resonantly enhanced multiphoton ionization time-of-flight methods have been used to investigate the photodissociation dynamics of the diatomic molecule Cl(2) following excitation to the first UV absorption band. The experimental results presented here are compared with high level time dependent wavepacket calculations performed on a set of ab initio potential energy curves [D. B. Kokh, A. B. Alekseyev, and R. J. Buenker, J. Chem. Phys. 120, 11549 (2004)]. The theoretical calculations provide the first determination of all dynamical information regarding the dissociation of a system of this complexity, including angular momentum polarization. Both low rank K = 1, 2 and high rank K = 3 electronic polarization are predicted to be important for dissociation into both asymptotic product channels and, in general, good agreement is found between the recent theory and the measurements made here, which include the first experimental determination of high rank K = 3 orientation

Structure-kinetic relationship reveals the mechanism of selectivity of FAK inhibitors over PYK2

There is increasing evidence of a significant correlation between prolonged drug-target residence time and increased drug efficacy. Here, we report a structural rationale for kinetic selectivity between two closely related kinases: focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). We found that slowly dissociating FAK inhibitors induce helical structure at the DFG motif of FAK but not PYK2. Binding kinetic data, high-resolution structures and mutagenesis data support the role of hydrophobic interactions of inhibitors with the DFG-helical region, providing a structural rationale for slow dissociation rates from FAK and kinetic selectivity over PYK2. Our experimental data correlate well with computed relative residence times from molecular simulations, supporting a feasible strategy for rationally optimizing ligand residence times. We suggest that the interplay between the protein structural mobility and ligand-induced effects is a key regulator of the kinetic selectivity of inhibitors of FAK versus PYK2