812 research outputs found
Chirality and Protein Folding
There are several simple criteria of folding to a native state in model
proteins. One of them involves crossing of a threshold value of the RMSD
distance away from the native state. Another checks whether all native contacts
are established, i.e. whether the interacting amino acids come closer than some
characteristic distance. We use Go-like models of proteins and show that such
simple criteria may prompt one to declare folding even though fragments of the
resulting conformations have a wrong sense of chirality. We propose that a
better condition of folding should augment the simple criteria with the
requirement that most of the local values of the chirality should be nearly
native. The kinetic discrepancy between the simple and compound criteria can be
substantially reduced in the Go-like models by providing the Hamiltonian with a
term which favors native values of the local chirality. We study the effects of
this term as a function of its amplitude and compare it to other models such as
with the side groups and with the angle-dependent potentials.Comment: To be published in a special issue of J. Phys.: Cond. Mat. (Bedlewo
Workshop
DOMAIN WALLS IN THE QUANTUM TRANSVERSE ISING MODEL
We discuss several problems concerning domain walls in the spin Ising
model at zero temperature in a magnetic field, , applied in the
direction. Some results are also given for the planar (-) model in a
transverse field. We treat the quantum problem in one dimension by perturbation
theory at small and numerically over a large range of . We obtain the
spin density profile by fixing the spins at opposite ends of the chain to have
opposite signs of . One dimension is special in that there the quantum
width of the wall is proportional to the size of the system. We also study
the quantitative features of the `particle' band which extends up to energies
of order above the ground state. Except for the planar limit, this particle
band is well separated from excitations having energy involving creation
of more walls. At large this particle band develops energy gaps and the
lowest sub-band has tunnel splittings of order . This scale of
energy gives rise to anomalous scaling with respect to a) finite size, b)
temperature, or c) random potentials. The intrinsic width of the domain wall
and the pinning energy are also defined and calculated in certain limiting
cases. The general conclusion is that quantum effects prevent the wall from
being sharp and in higher dimension would prevent sudden excursions in the
configuration of the wall.Comment: 40 pages and 13 figures, Phys. Rev. B, to be publishe
Coarse grained description of the protein folding
We consider two- and three-dimensional lattice models of proteins which were
characterized previously. We coarse grain their folding dynamics by reducing it
to transitions between effective states. We consider two methods of selection
of the effective states. The first method is based on the steepest descent
mapping of states to underlying local energy minima and the other involves an
additional projection to maximally compact conformations. Both methods generate
connectivity patterns that allow to distinguish between the good and bad
folders. Connectivity graphs corresponding to the folding funnel have few loops
and are thus tree-like. The Arrhenius law for the median folding time of a
16-monomer sequence is established and the corresponding barrier is related to
easily identifiable kinetic trap states.Comment: REVTeX, 9 pages, 15 EPS figures, to appear in Phys. Rev.
Energy landscapes, supergraphs, and "folding funnels" in spin systems
Dynamical connectivity graphs, which describe dynamical transition rates
between local energy minima of a system, can be displayed against the
background of a disconnectivity graph which represents the energy landscape of
the system. The resulting supergraph describes both dynamics and statics of the
system in a unified coarse-grained sense. We give examples of the supergraphs
for several two dimensional spin and protein-related systems. We demonstrate
that disordered ferromagnets have supergraphs akin to those of model proteins
whereas spin glasses behave like random sequences of aminoacids which fold
badly.Comment: REVTeX, 9 pages, two-column, 13 EPS figures include
Scaling of folding properties in simple models of proteins
Scaling of folding properties of proteins is studied in a toy system -- the
lattice Go model with various two- and three- dimensional geometries of the
maximally compact native states. Characteristic folding times grow as power
laws with the system size. The corresponding exponents are not universal.
Scaling of the thermodynamic stability also indicates size-related
deterioration of the folding properties.Comment: REVTeX, 4 pages, 4 EPS figures, PRL (in press
Localization and Interaction Effects in Strongly Underdoped La2-xSrxCuO4
The in-plane magnetoresistance (MR) in La2-xSrxCuO4 films with 0.03 < x <
0.05 has been studied in the temperature range 1.6 K to 100 K, and in magnetic
fields up to 14 T, parallel and perpendicular to the CuO2 planes. The behavior
of the MR is consistent with a predominant influence of interaction effects at
high temperatures, switching gradually to a regime dominated by spin scattering
at low T. Weak localization effects are absent. A positive orbital MR appears
close to the boundary between the antiferromagnetic and the spin-glass phase,
suggesting the onset of Maki-Thompson superconducting fluctuations deep inside
the insulating phase.Comment: 4 pages, 3 figures, to appear in Phys. Rev. Letter
Folding in two-dimenensional off-lattice models of proteins
Model off-lattice sequences in two dimensions are constructed so that their
native states are close to an on-lattice target. The Hamiltonian involves the
Lennard-Jones and harmonic interactions. The native states of these sequences
are determined with a high degree of certainty through Monte Carlo processes.
The sequences are characterized thermodynamically and kinetically. It is shown
that the rank-ordering-based scheme of the assignment of contact energies
typically fails in off-lattice models even though it generates high stability
of on-lattice sequences. Similar to the on-lattice case, Go-like modeling, in
which the interaction potentials are restricted to the native contacts in a
target shape, gives rise to good folding properties. Involving other contacts
deteriorates these properties.Comment: REVTeX, 9 pages, 8 EPS figure
Delineation of the Native Basin in Continuum Models of Proteins
We propose two approaches for determining the native basins in off-lattice
models of proteins. The first of them is based on exploring the saddle points
on selected trajectories emerging from the native state. In the second
approach, the basin size can be determined by monitoring random distortions in
the shape of the protein around the native state. Both techniques yield the
similar results. As a byproduct, a simple method to determine the folding
temperature is obtained.Comment: REVTeX, 6 pages, 5 EPS figure
Boundary conditions at a fluid - solid interface
We study the boundary conditions at a fluid-solid interface using molecular
dynamics simulations covering a broad range of fluid-solid interactions and
fluid densities, and both simple and chain-molecule fluids. The slip length is
shown to be independent of the type of flow, but rather is related to the fluid
organization near the solid, as governed by the fluid-solid molecular
interactions.Comment: REVtex, to appear in Physical Review Letter
Selective function-blocking monoclonal human antibody highlights the important role of membrane type-1 matrix metalloproteinase (MT1-MMP) in metastasis.
The invasion-promoting MT1-MMP is a cell surface-associated collagenase with a plethora of critical cellular functions. There is a consensus that MT1-MMP is a key protease in aberrant pericellular proteolysis in migrating cancer cells and, accordingly, a promising drug target. Because of high homology in the MMP family and a limited success in the design of selective small-molecule inhibitors, it became evident that the inhibitor specificity is required for selective and successful MT1-MMP therapies. Using the human Fab antibody library (over 1.25×109 individual variants) that exhibited the extended, 23-27 residue long, VH CDR-H3 segments, we isolated a panel of the inhibitory antibody fragments, from which the 3A2 Fab outperformed others as a specific and potent, low nanomolar range, inhibitor of MT1-MMP. Here, we report the in-depth characterization of the 3A2 antibody. Our multiple in vitro and cell-based tests and assays, and extensive structural modeling of the antibody/protease interactions suggest that the antibody epitope involves the residues proximal to the protease catalytic site and that, in contrast with tissue inhibitor-2 of MMPs (TIMP-2), the 3A2 Fab inactivates the protease functionality by binding to the catalytic domain outside the active site cavity. In agreement with the studies in metastasis by others, our animal studies in acute pulmonary melanoma metastasis support a key role of MT1-MMP in metastatic process. Conversely, the selective anti-MT1-MMP monotherapy significantly alleviated melanoma metastatic burden. It is likely that further affinity maturation of the 3A2 Fab will result in the lead inhibitor and a proof-of-concept for MT1-MMP targeting in metastatic cancers
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