The force required to rupture the streptavidin-biotin complex was calculated here by computer simulations. The computed force agrees well with that obtained by recent single molecule atomic force microscope experiments. These simulations suggest a detailed multiple-pathway rupture mechanism involving five major unbinding steps. Binding forces and specificity are attributed to a hydrogen bond network between the biotin ligand and residues within the binding pocket of streptavidin. During rupture, additional water bridges substantially enhance the stability of the complex and even dominate the binding interactions. In contrast, steric restraints do not appear to contribute to the binding forces, although conformational motions were observed.

We study electronic excitations in long polyenes, i.e. , in one-dimensional strongly correlated electron systems which are neither infinite nor small. The excitations are described within Hubbard and Pariser-Parr-Pople (PPP) models by means of a multiple-reference double-excitation expansion [P. Tavan and K. Schulten, J. Chem. Phys. S5, 6602 (1986)]. We find that quantized "transition" mornenta can be assigned to electronic excitations in finite chains. These momenta link excitation energies of finite chains to dispersion relations of infinite chains, i.e. , they bridge the gap between finite and infinite systems. A key result is the following: Excitation energies E in polyenes with X carbon atoms are described very accurately by the formula E~= AE~p+u~k (1V)q, q =1,2, . . . , where p denotes the excitation class, EEOC the energy gap in the infinite system [a~k(N)&0], and k(N) the elementary transition momentum. The parameters AEq~and a~a re determined for covalent and ionic excitations in alternating and nonalternating polyenes. The covalent excitations are combinations of triplet excitations T, i.e. , T, TT, TTT,~~~. The lowest singlet excitations in the infinite polyene, e.g. , in polyacetylene or polydiacetylene, are TT states.Available evidence proves that these states can dissociate into separate triplets. The bond structure of TT states is that of a neutral soliton-antisoliton pair. The level density of TT states in long polyenes is high enough to allow dissociation into separate solitons.

In neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and prion diseases, deposits of aggregated disease-specific proteins are found. Oligomeric aggregates are presumed to be the key neurotoxic agent. Here we describe the novel oligomer modulator anle138b [3-(1,3-benzodioxol-5-yl)-5-(3-bromophenyl)-1H-pyrazole], an aggregation inhibitor we developed based on a systematic high-throughput screening campaign combined with medicinal chemistry optimization. In vitro, anle138b blocked the formation of pathological aggregates of prion protein (PrPSc) and of α-synuclein (α-syn), which is deposited in PD and other synucleinopathies such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Notably, anle138b strongly inhibited all prion strains tested including BSE-derived and human prions. Anle138b showed structure-dependent binding to pathological aggregates and strongly inhibited formation of pathological oligomers in vitro and in vivo both for prion protein and α-synuclein. Both in mouse models of prion disease and in three different PD mouse models, anle138b strongly inhibited oligomer accumulation, neuronal degeneration, and disease progression in vivo. Anle138b had no detectable toxicity at therapeutic doses and an excellent oral bioavailability and blood–brain-barrier penetration. Our findings indicate that oligomer modulators provide a new approach for disease-modifying therapy in these diseases, for which only symptomatic treatment is available so far. Moreover, our findings suggest that pathological oligomers in neurodegenerative diseases share structural features, although the main protein component is disease-specific, indicating that compounds such as anle138b that modulate oligomer formation by targeting structure-dependent epitopes can have a broad spectrum of activity in the treatment of different protein aggregation diseases.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1114-9) contains supplementary material, which is available to authorized users.

We present a hybrid method for molecular dynamics simulations of solutes in complex solvents as represented, for example, by substrates within enzymes. The method combines a quantum mechanical ͑QM͒ description of the solute with a molecular mechanics ͑MM͒ approach for the solvent. The QM fragment of a simulation system is treated by ab initio density functional theory ͑DFT͒ based on plane-wave expansions. Long-range Coulomb interactions within the MM fragment and between the QM and the MM fragment are treated by a computationally efficient fast multipole method. For the description of covalent bonds between the two fragments, we introduce the scaled position link atom method ͑SPLAM͒, which removes the shortcomings of related procedures. The various aspects of the hybrid method are scrutinized through test calculations on liquid water, the water dimer, ethane and a small molecule related to the retinal Schiff base. In particular, the extent to which vibrational spectra obtained by DFT for the solute can be spoiled by the lower quality force field of the solvent is checked, including cases in which the two fragments are covalently joined. The results demonstrate that our QM/MM hybrid method is especially well suited for the vibrational analysis of molecules in condensed phase.

A correct description of the electronic excitations in polyenes demands that electron correlation is accounted for correctly. Very large expansions are necessary including manyelectron configurations with at least one, two, three, and four electrons promoted from the Hartree-Fock ground state. The enormous size of such expansions had prohibited accurate computations of the spectra for polyenes with more than ten 11" electrons. We present a multireference double excitation configuration interaction method (MRD-CI) which allows such computations for polyenes with up to 1611" electrons. We employ a Pariser-Parr-Pople (PPP) model Hamiltonian. For short polyenes with up to ten 11" electrons our calculations reproduce the excitation energies resulting from full-CI calculations. We extend our calculations to study the low-lying electronic excitations of the longer polyenes, in particular, the gap between the first optically forbidden and the first optically allowed excited singlet state. The size of this gap is shown to depend strongly on the degree of bond alternation and on the dielectric shielding of the Coulomb repulsion between the 11" electrons.6602

Femtosecond time-resolved spectroscopy on model peptides with built-in light switches combined with computer simulation of light-triggered motions offers an attractive integrated approach toward the understanding of peptide conformational dynamics. It was applied to monitor the light-induced relaxation dynamics occurring on subnanosecond time scales in a peptide that was backbone-cyclized with an azobenzene derivative as optical switch and spectroscopic probe. The femtosecond spectra permit the clear distinguishing and characterization of the subpicosecond photoisomerization of the chromophore, the subsequent dissipation of vibrational energy, and the subnanosecond conformational relaxation of the peptide. The photochemical cis͞trans-isomerization of the chromophore and the resulting peptide relaxations have been simulated with molecular dynamics calculations. The calculated reaction kinetics, as monitored by the energy content of the peptide, were found to match the spectroscopic data. Thus we verify that all-atom molecular dynamics simulations can quantitatively describe the subnanosecond conformational dynamics of peptides, strengthening confidence in corresponding predictions for longer time scales.

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Due to the progress of density functional theory (DFT) accurate computations of vibrational spectra of isolated molecules have become a standard task in computational chemistry. This is not yet the case for solution spectra. To contribute to the exploration of corresponding computational procedures, here we suggest a more efficient variant of the so-called instantaneous normal-mode analysis (INMA). This variant applies conventional molecular dynamics (MD) simulations, which are based on nonpolarizable molecular mechanics (MM) force fields, to the rapid generation of a large ensemble of different solvation shells for a solute molecule. Short hybrid simulations, in which the solute is treated by DFT and the aqueous solvent by MM, start from snapshots of the MM solute−solvent MD trajectory and yield a set of statistically independent hydration shells partially adjusted to the DFT/MM force field. Within INMA, these shells are kept fixed at their 300 K structures, line spectra are calculated from the DFT/MM Hessians of the solute, and its inhomogeneously broadened solution spectra are derived by second-order statistics. As our test application we have selected the phosphate ions HPO4 2- and H2PO4 - because sizable solvation effects are expected for the IR spectra of these strongly polarizable ions. The widths, intensities, and spectral positions of the calculated bands are compared with experimental IR spectra recorded by us for the purpose of checking the computational procedures. These comparisons provide insights into the merits and limitations of the available DFT/MM approach to the prediction of IR spectra in the condensed phase.