Internal protein dynamics shifts the distance to the mechanical transition state

Mechanical unfolding of polyproteins by force spectroscopy provides valuable insight into their free energy landscapes. Most experiments of the unfolding process have been fit to two-state and/or one dimensional models, with the details of the protein and its dynamics often subsumed into a zero-force unfolding rate and a distance x(u)(1D) to the transition state. We consider the entire phase space of a model protein under a constant force, and show that x(u)(1D) contains a sizeable contribution from exploring the full multidimensional energy landscape. This effect is greater for proteins with many degrees of freedom that are affected by force; and surprisingly, we predict that externally attached flexible linkers also contribute to the measured unfolding characteristics

s- and d-wave Symmetries in Nonadiabatic Theory of Superconductivity

High-$T_c$ superconductors have Fermi energies $E_F$ much smaller than conventional metals comparable to phonon frequencies. In such a situation nonadiabatic effects are important. A generalization of Eliashberg theory in the nonadiabatic regime has previously been shown to reproduce some anomalous features of the high-$T_c$ superconductors as for istance the enhancement of $T_c$ or the isotopic effects on $T_c$ and $m^*$. In this contribution we address the issue of the symmetry of the gap in the context of nonadiabatic superconductivity. We show that vertex corrections have a momentum structure which favours d-wave superconductivity when forward scattering is predominant. An additional increase of $T_c$ is also found.Comment: 6 pages, 3 eps figure, ijmpb-macros, proceeding of SATT10, to appear on Int. Journ. Mod. Phys.

Isotope effects in the Hubbard-Holstein model within dynamical mean-field theory

We study the isotope effects arising from the coupling of correlated electrons with dispersionless phonons by considering the Hubbard-Holstein model at half-filling within the dynamical mean-field theory. In particular we calculate the isotope effects on the quasi-particle spectral weight $Z$, the renormalized phonon frequency, and the static charge and spin susceptibilities. In the weakly correlated regime $U/t \lesssim 1.5$, where $U$ is the Hubbard repulsion and $t$ is the bare electron half-bandwidth, the physical properties are qualitatively similar to those characterizing the Holstein model in the absence of Coulomb repulsion, where the bipolaronic binding takes place at large electron-phonon coupling, and it reflects in divergent isotope responses. On the contrary in the strongly correlated regime $U/t \gtrsim 1.5$, where the bipolaronic metal-insulator transition becomes of first order, the isotope effects are bounded, suggesting that the first order transition is likely driven by an electronic mechanism, rather then by a lattice instability. These results point out how the isotope responses are extremely sensitive to phase boundaries and they may be used to characterize the competition between the electron-phonon coupling and the Hubbard repulsion.Comment: 10 pages, 8 figures. The paper has been already accepted on Phys. Rev.

Nonadiabatic high-Tc superconductivity in hole-doped fullerenes

In this paper we address the possibility of high-T-c superconductivity (T(c)similar to100 K) in hypothetical hole doped C-60 within the context of the nonadiabatic theory of superconductivity. Our analysis shows that electron doped fullerenes, represented by the A(3)C(60) family, are characterized by relatively small values of the electron-phonon coupling constant lambda, which can thus be further increased by hole doping before lattice instabilities occur. In particular we show that T-c larger than 100 K are compatible in the nonadiabatic context with microscopic parameters lambda(h)similar or equal to0.5-1.0, mu(*)similar or equal to0.3-0.5 and phonon frequencies omega(ph)similar or equal to1500-2000 K. These results provide a stimulus for material engineering and optimization along the lines indicated

Relevance of multiband Jahn-Teller effects on the electron-phonon interaction in A3A_3C60_{60}

Assessing the effective relevance of multiband effects in the fullerides is of fundamental importance to understand the complex superconducting and transport properties of these compounds. In this paper we investigate in particular the role of the multiband effects on the electron-phonon (el-ph) properties of the $t_{1u}$ bands coupled with the Jahn-Teller intra-molecular $H_g$ vibrational modes in the C$_{60}$ compounds. We show that, assuming perfect degeneracy of the electronic bands, vertex diagrams arising from the breakdown of the adiabatic hypothesis, are one order of magnitude smaller than the non-crossing terms usually retained in the Migdal-Eliashberg (ME) theory. These results permit to understand the robustness on ME theory found by numerical calculations. The effects of the non degeneracy of the $t_{1u}$ in realistic systems are also analyzed. Using a tight-binding model we show that the el-ph interaction is mainly dominated by interband scattering within a single electronic band. Our results question the reliability of a degenerate band modeling and show the importance of these combined effects in the $A_3$C$_{60}$ family.Comment: 5 pages, 3 eps figure

Donor-strand exchange in chaperone-assisted pilus assembly revealed in atomic detail by molecular dynamics

Adhesive multi-subunit fibres are assembled on the surface of many pathogenic bacteria via the chaperone-usher pathway. In the periplasm, a chaperone donates a β-strand to a pilus subunit to complement its incomplete immunoglobulin-like fold. At the outer membrane, this is replaced with a β-strand formed from the N-terminal extension (Nte) of an incoming pilus subunit by a donorstrand exchange (DSE) mechanism. This reaction has previously been shown to proceed via a concerted mechanism, in which the Nte interacts with the chaperone:subunit complex before the chaperone has been displaced, forming a ternary intermediate. Thereafter, the pilus and chaperone β-strands have been postulated to undergo a strand swap by a ‘zip-in-zip-out’ mechanism, whereby the chaperone strand zips out, residue by residue, as the Nte simultaneously zips in. Here, molecular dynamics simulations have been used to probe the DSE mechanism during formation of the Salmonella enterica Saf pilus at an atomic level, allowing the direct investigation of the zip-inzip- out hypothesis. The simulations provide an explanation of how the incoming Nte is able to dock and initiate DSE due to inherent dynamic fluctuations within the chaperone:subunit complex. The chaperone donor-strand is shown to unbind from the pilus subunit residue by residue, in direct support of the zip-in-zip-out hypothesis. In addition, an interaction of a residue towards the Nterminus of the Nte with a specific binding pocket (P*) on the adjacent pilus subunit is shown to stabilise the DSE product against unbinding, which also proceeds by a zippering mechanism. Together, the study provides an in-depth picture of DSE, including the first insights into the molecular events occurring during the zip-in-zip-out mechanism

Polaronic and nonadiabatic phase diagram from anomalous isotope effects

Isotope effects (IEs) are powerful tool to probe directly the dependence of many physical properties on the lattice dynamics. In this paper we invenstigate the onset of anomalous IEs in the spinless Holstein model by employing the dynamical mean field theory. We show that the isotope coefficients of the electron effective mass and of the dressed phonon frequency are sizeable also far away from the strong coupling polaronic crossover and mark the importance of nonadiabatic lattice fluctuations in the weak to moderate coupling region. We characterize the polaronic regime by the appearence of huge IEs. We draw a nonadiabatic phase diagram in which we identify a novel crossover, not related to polaronic features, where the IEs attain their largest anomalies.Comment: 5 pages, 4 figure

Assessment of ab initio models of protein complexes by molecular dynamics.

Determining how proteins interact to form stable complexes is of crucial importance, for example in the development of novel therapeutics. Computational methods to determine the thermodynamically stable conformation of complexes from the structure of the binding partners, such as RosettaDock, might potentially emerge to become a promising alternative to traditional structure determination methods. However, while models virtually identical to the correct experimental structure can in some cases be generated, the main difficulty remains to discriminate correct or approximately correct models from decoys. This is due to the ruggedness of the free-energy landscape, the approximations intrinsic in the scoring functions, and the intrinsic flexibility of proteins. Here we show that molecular dynamics simulations performed starting from a number top-scoring models can not only discriminate decoys and identify the correct structure, but may also provide information on an initial map of the free energy landscape that elucidates the binding mechanism

Computational Modeling of Designed Ankyrin Repeat Protein Complexes with their Targets

Recombinant therapeutic proteins are playing an ever-increasing role in the clinic. High-affinity binding candidates can be produced in a high-throughput manner through the process of selection and evolution from large libraries, but the structures of the complexes with target protein can only be determined for a small number of them in a costly, low-throughput manner, typically by x-ray crystallography. Reliable modeling of complexes would greatly help to understand their mode of action and improve them by further engineering, for example, by designing bi-paratopic binders. Designed ankyrin repeat proteins (DARPins) are one such class of antibody mimetics that have proven useful in the clinic, in diagnostics and research. Here we have developed a standardized procedure to model DARPin–target complexes that can be used to predict the structures of unknown complexes. It requires only the sequence of a DARPin and a structure of the unbound target. The procedure includes homology modeling of the DARPin, modeling of the flexible parts of a target, rigid body docking to ensembles of the target and docking with a partially flexible backbone. For a set of diverse DARPin–target complexes tested it generated a single model of the complex that well approximates the native state of the complex. We provide a protocol that can be used in a semi-automated way and with tools that are freely available. The presented concepts should help to accelerate the development of novel bio-therapeutics for scaffolds with similar properties

The Role of High-Dimensional Diffusive Search, Stabilization, and Frustration in Protein Folding

Proteins are polymeric molecules with many degrees of conformational freedom whose internal energetic interactions are typically screened to small distances. Therefore, in the high-dimensional conformation space of a protein, the energy landscape is locally relatively flat, in contrast to low-dimensional representations, where, because of the induced entropic contribution to the full free energy, it appears funnel-like. Proteins explore the conformation space by searching these flat subspaces to find a narrow energetic alley that we call a hypergutter and then explore the next, lower-dimensional, subspace. Such a framework provides an effective representation of the energy landscape and folding kinetics that does justice to the essential characteristic of high-dimensionality of the search-space. It also illuminates the important role of nonnative interactions in defining folding pathways. This principle is here illustrated using a coarse-grained model of a family of three-helix bundle proteins whose conformations, once secondary structure has formed, can be defined by six rotational degrees of freedom. Two folding mechanisms are possible, one of which involves an intermediate. The stabilization of intermediate subspaces (or states in low-dimensional projection) in protein folding can either speed up or slow down the folding rate depending on the amount of native and nonnative contacts made in those subspaces. The folding rate increases due to reduced-dimension pathways arising from the mere presence of intermediate states, but decreases if the contacts in the intermediate are very stable and introduce sizeable topological or energetic frustration that needs to be overcome. Remarkably, the hypergutter framework, although depending on just a few physically meaningful parameters, can reproduce all the types of experimentally observed curvature in chevron plots for realizations of this fold