41 research outputs found
Fitting a function to time-dependent ensemble averaged data
Time-dependent ensemble averages, i.e., trajectory-based averages of some
observable, are of importance in many fields of science. A crucial objective
when interpreting such data is to fit these averages (for instance, squared
displacements) with a function and extract parameters (such as diffusion
constants). A commonly overlooked challenge in such function fitting procedures
is that fluctuations around mean values, by construction, exhibit temporal
correlations. We show that the only available general purpose function fitting
methods, correlated chi-square method and the weighted least squares method
(which neglects correlation), fail at either robust parameter estimation or
accurate error estimation. We remedy this by deriving a new closed-form error
estimation formula for weighted least square fitting. The new formula uses the
full covariance matrix, i.e., rigorously includes temporal correlations, but is
free of the robustness issues, inherent to the correlated chi-square method. We
demonstrate its accuracy in four examples of importance in many fields:
Brownian motion, damped harmonic oscillation, fractional Brownian motion and
continuous time random walks. We also successfully apply our method, weighted
least squares including correlation in error estimation (WLS-ICE), to particle
tracking data. The WLS-ICE method is applicable to arbitrary fit functions, and
we provide a publically available WLS-ICE software.Comment: 47 pages (main text: 15 pages, supplementary: 32 pages
Three-helix-bundle Protein in a Ramachandran Model
We study the thermodynamic behavior of a model protein with 54 amino acids
that forms a three-helix bundle in its native state. The model contains three
types of amino acids and five to six atoms per amino acid and has the
Ramachandran torsional angles , as its degrees of freedom. The
force field is based on hydrogen bonds and effective hydrophobicity forces. For
a suitable choice of the relative strength of these interactions, we find that
the three-helix-bundle protein undergoes an abrupt folding transition from an
expanded state to the native state. Also shown is that the corresponding one-
and two-helix segments are less stable than the three-helix sequence.Comment: 15 pages, 7 figure
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
Sequence Dependence of Self-Interacting Random Chains
We study the thermodynamic behavior of the random chain model proposed by
Iori, Marinari and Parisi, and how this depends on the actual sequence of
interactions along the chain. The properties of randomly chosen sequences are
compared to those of designed ones, obtained through a simulated annealing
procedure in sequence space. We show that the transition to the folded phase
takes place at a smaller strength of the quenched disorder for designed
sequences. As a result, folding can be relatively fast for these sequences.Comment: 14 pages, uuencoded compressed postscript fil
Viscosities of Quark-Gluon Plasmas
The quark and gluon viscosities are calculated in quark-gluon plasmas to
leading orders in the coupling constant by including screening. For weakly
interaction QCD and QED plasmas dynamical screening of transverse interactions
and Debye screening of longitudinal interactions controls the infrared
divergences. For strongly interacting plasmas other screening mechanisms taken
from lattice calculations are employed. By solving the Boltzmann equation for
quarks and gluons including screening the viscosity is calculated to leading
orders in the coupling constant. The leading logarithmic order is calculated
exactly by a full variational treatment. The next to leading orders are found
to be very important for sizable coupling constants as those relevant for the
transport properties relevant for quark-gluon plasmas created in relativistic
heavy ion collisions and the early universe.Comment: 12 pages + 6 figures, report LBL-3492
The Instanton Density at Finite Temperatures
For {\it low} T new strict results for the instanton density n(T) are
reported. Using the PCAC methods, we express n(T) in terms of {\it vacuum}
average values of certain operators, times their {\it calculated} T-dependence.
At high T, we discuss the {\it applicability} limits of the perturbative
results. We further speculate about possible behaviour of n(T) at
Note on irreducible approach to reducible second-class constraints
An irreducible canonical approach to reducible second-class constraints is
given. The procedure is illustrated on gauge-fixed two-forms.Comment: Latex 2.09, 9 pages, to appear in Europhys. Let
β-hairpin-mediated formation of structurally distinct multimers of neurotoxic prion peptides
Protein misfolding disorders are associated with conformational changes in specific proteins, leading to the formation of potentially neurotoxic amyloid fibrils. During pathogenesis of prion disease, the prion protein misfolds into β-sheet rich, protease-resistant isoforms. A key, hydrophobic domain within the prion protein, comprising residues 109–122, recapitulates many properties of the full protein, such as helix-to-sheet structural transition, formation of fibrils and cytotoxicity of the misfolded isoform. Using all-atom, molecular simulations, it is demonstrated that the monomeric 109–122 peptide has a preference for α-helical conformations, but that this peptide can also form β-hairpin structures resulting from turns around specific glycine residues of the peptide. Altering a single amino acid within the 109–122 peptide (A117V, associated with familial prion disease) increases the prevalence of β-hairpin formation and these observations are replicated in a longer peptide, comprising residues 106–126. Multi-molecule simulations of aggregation yield different assemblies of peptide molecules composed of conformationally-distinct monomer units. Small molecular assemblies, consistent with oligomers, comprise peptide monomers in a β-hairpin-like conformation and in many simulations appear to exist only transiently. Conversely, larger assemblies are comprised of extended peptides in predominately antiparallel β-sheets and are stable relative to the length of the simulations. These larger assemblies are consistent with amyloid fibrils, show cross-β structure and can form through elongation of monomer units within pre-existing oligomers. In some simulations, assemblies containing both β-hairpin and linear peptides are evident. Thus, in this work oligomers are on pathway to fibril formation and a preference for β-hairpin structure should enhance oligomer formation whilst inhibiting maturation into fibrils. These simulations provide an important new atomic-level model for the formation of oligomers and fibrils of the prion protein and suggest that stabilization of β-hairpin structure may enhance cellular toxicity by altering the balance between oligomeric and fibrillar protein assemblies
Multiscale Coarse-Graining of the Protein Energy Landscape
A variety of coarse-grained (CG) models exists for simulation of proteins. An outstanding problem is the construction of a CG model with physically accurate conformational energetics rivaling all-atom force fields. In the present work, atomistic simulations of peptide folding and aggregation equilibria are force-matched using multiscale coarse-graining to develop and test a CG interaction potential of general utility for the simulation of proteins of arbitrary sequence. The reduced representation relies on multiple interaction sites to maintain the anisotropic packing and polarity of individual sidechains. CG energy landscapes computed from replica exchange simulations of the folding of Trpzip, Trp-cage and adenylate kinase resemble those of other reduced representations; non-native structures are observed with energies similar to those of the native state. The artifactual stabilization of misfolded states implies that non-native interactions play a deciding role in deviations from ideal funnel-like cooperative folding. The role of surface tension, backbone hydrogen bonding and the smooth pairwise CG landscape is discussed. Ab initio folding aside, the improved treatment of sidechain rotamers results in stability of the native state in constant temperature simulations of Trpzip, Trp-cage, and the open to closed conformational transition of adenylate kinase, illustrating the potential value of the CG force field for simulating protein complexes and transitions between well-defined structural states
Insights into Ligand–Protein Binding from Local Mechanical Response
Computational studies of ligand–protein binding are crucial for properly designing novel compounds of potential pharmacological interest. In this respect, researchers are increasingly interested in steered molecular dynamics for ligand–protein binding and unbinding studies. In particular, it has been suggested that analyzing the work profiles along the ligand–protein undocking paths could be fruitful. Here, we propose that small portions of work profiles, termed “local mechanical responses” of the system to a steering force, could serve as a universal measure for capturing relevant information about the system under investigation. Specifically, we first collected a high number of steering trajectories using two biological systems of increasing complexity (i.e., alanine dipeptide and (R)-roscovitine/CDK5 complex). Then, we devised a novel postprocessing tool to be applied to the local mechanical responses, to extract structural information related to the biological processes under investigation. Despite the out-of-equilibrium character of the trajectories, the analysis carried out on the work profiles provided pivotal information about the investigated biological processes. This could eventually be applied to drug design