The aggregation of alpha-synuclein (AS) is a critical step in the etiology of Parkinson's disease (PD). A central, unresolved question in the pathophysiology of PD relates to the role of AS-metal interactions in amyloid fibril formation and neurodegeneration. Our previous works established a hierarchy in alpha-synuclein-metal ion interactions, where Cu(II) binds specifically to the protein and triggers its aggregation under conditions that might be relevant for the development of PD. Two independent, non-interacting copper-binding sites were identified at the N-terminal region of AS, with significant difference in their affinities for the metal ion. In this work we have solved unknown details related to the structural binding specificity and aggregation enhancement mediated by Cu(II). The high-resolution structural characterization of the highest affinity N-terminus AS-Cu(II) complex is reported here. Through the measurement of AS aggregation kinetics we proved conclusively that the copper-enhanced AS amyloid formation is a direct consequence of the formation of the AS-Cu(II) complex at the highest affinity binding site. The kinetic behavior was not influenced by the His residue at position 50, arguing against an active role for this residue in the structural and biological events involved in the mechanism of copper-mediated AS aggregation. These new findings are central to elucidate the mechanism through which the metal ion participates in the fibrillization of AS and represent relevant progress in the understanding of the bioinorganic chemistry of PD.

Fast lateral proton migration along membranes is of vital importance for cellular energy homeostasis and various proton-coupled transport processes. It can only occur if attractive forces keep the proton at the interface. How to reconcile this high affinity to the membrane surface with high proton mobility is unclear. Here, we tested whether a minimalistic model interface between an apolar hydrophobic phase (n-decane) and an aqueous phase mimics the biological pathway for lateral proton migration. The observed diffusion span, on the order of tens of micrometers, and the high proton mobility were both similar to the values previously reported for lipid bilayers. Extensive ab initio simulations on the same water∕n-decane interface reproduced the experimentally derived free energy barrier for the excess proton. The free energy profile G H þ adopts the shape of a well at the interface, having a width of two water molecules and a depth of 6 AE 2RT . The hydroniums in direct contact with n-decane have a reduced mobility. However, the hydroniums in the second layer of water molecules are mobile. Their in silico diffusion coefficient matches that derived from our in vitro experiments, ð5.7 AE 0.7Þ × 10 −5 cm 2 s −1 . Conceivably, these are the protons that allow for fast diffusion along biological membranes.hydrophobic liquid | hydrophilic liquid interface | surface acidity | free energy calculations

The enzymatic polymerization of DNA and RNA is the basis for genetic inheritance for all living organisms. It is catalyzed by the DNA/RNA polymerase (Pol) superfamily. Here, bioinformatics analysis reveals that the incoming nucleotide substrate always forms an H-bond between its 3'-OH and β-phosphate moieties upon formation of the Michaelis complex. This previously unrecognized H-bond implies a novel self-activated mechanism (SAM), which synergistically connects the in situ nucleophile formation with subsequent nucleotide addition and, importantly, nucleic acid translocation. Thus, SAM allows an elegant and efficient closed-loop sequence of chemical and physical steps for Pol catalysis. This is markedly different from previous mechanistic hypotheses. Our proposed mechanism is corroborated via ab initio QM/MM simulations on a specific Pol, the human DNA polymerase-η, an enzyme involved in repairing damaged DNA. The structural conservation of DNA and RNA Pols supports the possible extension of SAM to Pol enzymes from the three domains of life.

A typical feature of spontaneous collapse models which aim at localizing wavefunctions in space is the violation of the principle of energy conservation. In the models proposed in the literature the stochastic field which is responsible for the localization mechanism causes the momentum to behave like a Brownian motion, whose larger and larger fluctuations show up as a steady increase of the energy of the system. In spite of the fact that, in all situations, such an increase is small and practically undetectable, it is an undesirable feature that the energy of physical systems is not conserved but increases constantly in time, diverging for t → ∞. In this paper we show that this property of collapse models can be modified: we propose a model of spontaneous wavefunction collapse sharing all most important features of usual models but such that the energy of isolated systems reaches an asymptotic finite value instead of increasing with a steady rate.

We analyze the recently proposed mirror superposition experiment of Marshall, Simon, Penrose, and Bouwmeester, assuming that the mirror's dynamics contains a nonunitary term of the Lindblad-type proportional to -[q,[q,rho]], with q the position operator for the center of mass of the mirror, and rho the statistical operator. We derive an exact formula for the fringe visibility for this system. We discuss the consequences of our result for tests of environmental decoherence and of collapse models. In particular, we find that with the conventional parameters for the continuous spontaneous localization model of state vector collapse, maintenance of coherence is expected to within an accuracy of at least 1 part in 10(8). Increasing the apparatus coupling to environmental decoherence may lead to observable modifications of the fringe visibility, with time dependence given by our exact result.

We present a flexible and efficient framework for multiscale modeling in computational chemistry (MiMiC). It is based on a multiple-program multiple-data (MPMD) 1 model with loosely coupled programs. Fast data exchange between programs is achieved through the use of MPI intercommunicators. This allows exploiting the existing parallelization strategies used by the coupled programs while maintaining a high degree of flexibility. MiMiC has been used in a new electrostatic embedding quantum mechanics/molecular mechanics (QM/MM) implementation coupling the highly efficient CPMD and GROMACS programs but it can also be extended to use other programs.The framework can also be utilized to extend the partitioning of the system into several domains that can be treated using different models, such as models based on wave function or density functional theory as well as coarse-graining and continuum models. The new QM/MM implementation treats long-range electrostatic QM-MM interactions through the multipoles of the QM subsystem which substantially reduces the computational cost without loss of accuracy compared to an exact treatment. This enables QM/MM molecular dynamics (MD) simulations of very large systems.

Native electrospray ionization/ion mobility-mass spectrometry (ESI/IM-MS) allows an accurate determination of low-resolution structural features of proteins. Yet, the presence of proton dynamics, observed already by us for DNA in the gas phase, and its impact on protein structural determinants, have not been investigated so far. Here, we address this issue by a multistep simulation strategy on a pharmacologically relevant peptide, the N-terminal residues of amyloid-β peptide (Aβ(1-16)). Our calculations reproduce the experimental maximum charge state from ESI-MS and are also in fair agreement with collision cross section (CCS) data measured here by ESI/IM-MS. Although the main structural features are preserved, subtle conformational changes do take place in the first ∼0.1 ms of dynamics. In addition, intramolecular proton dynamics processes occur on the picosecond-time scale in the gas phase as emerging from quantum mechanics/molecular mechanics (QM/MM) simulations at the B3LYP level of theory. We conclude that proton transfer phenomena do occur frequently during fly time in ESI-MS experiments (typically on the millisecond time scale). However, the structural changes associated with the process do not significantly affect the structural determinants.

We analyze the geometric phase for an open quantum system when computed by resorting to a stochastic unravelling of the reduced density matrix (quantum jump approach or stochastic Schrödinger equations). We show that the resulting phase strongly depends on the type of unravelling used for the calculations: as such, this phase is not a geometric object since it depends on non-physical parameters which are not related to the path followed by the density matrix during the evolution of the system.