105 research outputs found
Folding thermodynamics of model four-strand antiparallel beta-sheet proteins
The thermodynamic properties for three different types of off-lattice
four-strand beta-sheet protein models interacting via a hybrid Go-type
potential have been investigated. Discontinuous molecular dynamic simulations
have been performed for different sizes of the bias gap g, an artificial
measure of a model protein's preference for its native state. The thermodynamic
transition temperatures are obtained by calculating the squared radius of
gyration, the root-mean-squared pair separation fluctuation, the specific heat,
the internal energy of the system, and the Lindemann disorder parameter. In
spite of the simplicity, the protein-like heteropolymers have shown a complex
set of protein transitions as observed in experimental studies. Starting from
high temperature, these transitions include a collapse transition, a
disordered-to-ordered globule transition, a folding transition, and a
liquid-to-solid transition. These transitions strongly depend on the
native-state geometry of the model proteins and the size of the bias gap. A
strong transition from the disordered globule state to the ordered globule
state with large energy change and a weak transition from the ordered globule
state to the native state with small energy change were observed for the large
gap models. For the small gap models no native structures were observed at any
temperature, all three beta-sheet proteins fold into a partially-ordered
globule state which is geometrically different from the native state. For small
bias gaps at even lower temperatures, all protein motions are frozen indicating
an inactive solid-like phase.Comment: PDF file, 32 pages including 13 figure page
Conformational study of the protegrin-1 (PG-1) dimer interaction with lipid bilayers and its effect
BACKGROUND: Protegrin-1 (PG-1) is known as a potent antibiotic peptide; it prevents infection via an attack on the membrane surface of invading microorganisms. In the membrane, the peptide forms a pore/channel through oligomerization of multiple subunits. Recent experimental and computational studies have increasingly unraveled the molecular-level mechanisms underlying the interactions of the PG-1 β-sheet motifs with the membrane. The PG-1 dimer is important for the formation of oligomers, ordered aggregates, and for membrane damaging effects. Yet, experimentally, different dimeric behavior has been observed depending on the environment: antiparallel in the micelle environment, and parallel in the POPC bilayer. The experimental structure of the PG-1 dimer is currently unavailable. RESULTS: Although the β-sheet structures of the PG-1 dimer are less stable in the bulk water environment, the dimer interface is retained by two intermolecular hydrogen bonds. The formation of the dimer in the water environment implies that the pathway of the dimer invasion into the membrane can originate from the bulk region. In the initial contact with the membrane, both the antiparallel and parallel β-sheet conformations of the PG-1 dimer are well preserved at the amphipathic interface of the lipid bilayer. These β-sheet structures illustrate the conformations of PG-1 dimer in the early stage of the membrane attack. Here we observed that the activity of PG-1 β-sheets on the bilayer surface is strongly correlated with the dimer conformation. Our long-term goal is to provide a detailed mechanism of the membrane-disrupting effects by PG-1 β-sheets which are able to attack the membrane and eventually assemble into the ordered aggregates. CONCLUSION: In order to understand the dimeric effects leading to membrane damage, extensive molecular dynamics (MD) simulations were performed for the β-sheets of the PG-1 dimer in explicit water, salt, and lipid bilayers composed of POPC lipids. Here, we studied PG-1 dimers when organized into a β-sheet motif with antiparallel and parallel β-sheet arrangements in an NCCN packing mode. We focus on the conformations of PG-1 dimers in the lipid bilayer, and on the correlation between the conformations and the membrane disruption effects by PG-1 dimers. We investigate equilibrium structures of the PG-1 dimers in different environments in the early stage of the dimer invasion. The dimer interface of the antiparallel β-sheets is more stable than the parallel β-sheets, similar to the experimental observation in micelle environments. However, we only observe membrane disruption effects by the parallel β-sheets of the PG-1 dimer. This indicates that the parallel β-sheets interact with the lipids with the β-sheet plane lying obliquely to the bilayer surface, increasing the surface pressure in the initial insertion into the lipid bilayer. Recent experimental observation verified that parallel PG-1 dimer is biologically more active to insert into the POPC lipid bilayer
Protein Folding Pathways and Kinetics: Molecular Dynamics Simulations of β-Strand Motifs
AbstractThe folding pathways and the kinetic properties for three different types of off-lattice four-strand antiparallel β-strand protein models interacting via a hybrid Go-type potential have been investigated using discontinuous molecular dynamics simulations. The kinetic study of protein folding was conducted by temperature quenching from a denatured or random coil state to a native state. The progress parameters used in the kinetic study include the squared radius of gyration Rg2, the fraction of native contacts within the protein as a whole Q, and between specific strands Qab. In the time series of folding, the denatured proteins undergo a conformational change toward the native state. The model proteins exhibit a variety of kinetic folding pathways that include a fast-track folding pathway without passing through an intermediate and multiple pathways with trapping into more than one intermediate. The kinetic folding behavior of the β-strand proteins strongly depends on the native-state geometry of the model proteins and the size of the bias gap g, an artificial measure of a model protein's preference for its native state
Role of the fast kinetics of pyroglutamate-modified amyloid-β oligomers in membrane binding and membrane permeability.
Membrane permeability to ions and small molecules is believed to be a critical step in the pathology of Alzheimer's disease (AD). Interactions of oligomers formed by amyloid-β (Aβ) peptides with the plasma cell membrane are believed to play a fundamental role in the processes leading to membrane permeability. Among the family of Aβs, pyroglutamate (pE)-modified Aβ peptides constitute the most abundant oligomeric species in the brains of AD patients. Although membrane permeability mechanisms have been studied for full-length Aβ1-40/42 peptides, these have not been sufficiently characterized for the more abundant AβpE3-42 fragment. Here we have compared the adsorbed and membrane-inserted oligomeric species of AβpE3-42 and Aβ1-42 peptides. We find lower concentrations and larger dimensions for both species of membrane-associated AβpE3-42 oligomers. The larger dimensions are attributed to the faster self-assembly kinetics of AβpE3-42, and the lower concentrations are attributed to weaker interactions with zwitterionic lipid headgroups. While adsorbed oligomers produced little or no significant membrane structural damage, increased membrane permeabilization to ionic species is understood in terms of enlarged membrane-inserted oligomers. Membrane-inserted AβpE3-42 oligomers were also found to modify the mechanical properties of the membrane. Taken together, our results suggest that membrane-inserted oligomers are the primary species responsible for membrane permeability
Structural Convergence Among Diverse, Toxic β-Sheet Ion Channels
Recent studies show that an array of -sheet peptides, including N-terminally truncated A peptides (A11-42/17-42), K3 (a 2-microglobulin fragment), and protegrin-1 (PG-1) peptides form ion channel-like structures and elicit single channel ion conductance when reconstituted in lipid bilayers and induce cell damage through cell calcium overload. Striking similarities are observed in the dimensions of these toxic channels irrespective of their amino acid sequences. However, the intriguing question of preferred channel sizes is still unresolved. Here, exploiting ssNMR-based, U-shaped, -strand-turn--strand coordinates, we modeled truncated A peptide (p3) channels with different sizes (12- to 36-mer). Molecular dynamics (MD) simulations show that optimal channel sizes of the ion channels presenting toxic ionic flux range between 16- and 24-mer. This observation is in good agreement with channel dimensions imaged by AFM for A9-42, K3 fragment, and PG-1 channels and highlights the bilayer-supported preferred toxic -channel sizes and organization, regardless of the peptide sequence
Mechanism of activation and the rewired network: New drug design concepts
Precision oncology benefits from effective early phase drug discovery decisions. Recently, drugging inactive protein conformations has shown impressive successes, raising the cardinal questions of which targets can profit and what are the principles of the active/inactive protein pharmacology. Cancer driver mutations have been established to mimic the protein activation mechanism. We suggest that the decision whether to target an inactive (or active) conformation should largely rest on the protein mechanism of activation. We next discuss the recent identification of double (multiple) same-allele driver mutations and their impact on cell proliferation and suggest that like single driver mutations, double drivers also mimic the mechanism of activation. We further suggest that the structural perturbations of double (multiple) in cis mutations may reveal new surfaces/pockets for drug design. Finally, we underscore the preeminent role of the cellular network which is deregulated in cancer. Our structure-based review and outlook updates the traditional Mechanism of Action, informs decisions, and calls attention to the intrinsic activation mechanism of the target protein and the rewired tumor-specific network, ushering innovative considerations in precision medicine
Exchange anisotropy and the dynamic phase transition in thin ferromagnetic Heisenberg films
Monte Carlo simulations have been performed to investigate the dependence of
the dynamic phase behavior on the bilinear exchange anisotropy of a classical
Heisenberg spin system. The system under consideration is a planar thin
ferromagnetic film with competing surface fields subject to a pulsed
oscillatory external field. The results show that the films exhibit a single
discontinuous dynamic phase transition (DPT) as a function of the anisotropy of
the bilinear exchange interaction in the Hamiltonian. Furthermore there is no
evidence of stochastic resonance (SR) associated with the DPT. These results
are in marked contrast to the continuous DPT observed in the same system as a
function of temperature and applied field strength for a fixed bilinear
exchange anisotropy.Comment: 11 pages including 3 figure pages; submitted to PR
Hysteresis and the dynamic phase transition in thin ferromagnetic films
Hysteresis and the non-equilibrium dynamic phase transition in thin magnetic
films subject to an oscillatory external field have been studied by Monte Carlo
simulation. The model under investigation is a classical Heisenberg spin system
with a bilinear exchange anisotropy in a planar thin film geometry with
competing surface fields. The film exhibits a non-equilibrium phase transition
between dynamically ordered and dynamically disordered phases characterized by
a critical temperature Tcd, whose location of is determined by the amplitude H0
and frequency w of the applied oscillatory field. In the presence of competing
surface fields the critical temperature of the ferromagnetic-paramagnetic
transition for the film is suppressed from the bulk system value, Tc, to the
interface localization-delocalization temperature Tci. The simulations show
that in general Tcd < Tci for the model film. The profile of the time-dependent
layer magnetization across the film shows that the dynamically ordered and
dynamically disordered phases coexist within the film for T < Tcd. In the
presence of competing surface fields, the dynamically ordered phase is
localized at one surface of the film.Comment: PDF file, 21 pages including 8 figure pages; added references,typos
added; to be published in PR
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