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Current
Protein & Peptide Science
ISSN: 1389-2042
Current Protein and Peptide
Science
Volume 9, Number 1, February 2008
Contents
Recent Progress and Future Directions in Protein-Protein
Docking Pp. 1-15
David W. Ritchie
[Abstract]
Activation, Exposure and Penetration of Virally
Encoded, Membrane-Active Polypeptides During Non-Enveloped
Virus Entry Pp. 16-27
Manidipa Banerjee and John E. Johnson
[Abstract]
Proteins As Networks: Usefulness of Graph Theory
in Protein Science Pp. 28-38
Arun Krishnan, Joseph P. Zbilut, Masaru Tomita and Alessandro
Giuliani
[Abstract]
Lantibiotic Immunity Pp. 39-49
Lorraine A. Draper, R. Paul Ross, Colin Hill and Paul
D. Cotter
[Abstract]
NMR of Membrane-Associated Peptides and Proteins
Pp. 50-69
Guangshun Wang
[Abstract]
Homology-Free Prediction of Functional Class
of Proteins and Peptides by Support Vector Machines Pp.
70-95
F. Zhu, L.Y. Han, X. Chen, H.H. Lin, S. Ong, B. Xie, H.L.
Zhang and Y.Z. Chen
[Abstract]
Structure, Function and Biological Relevance
of Prolyl Oligopeptidase Pp. 96-107
Zoltán Szeltner and László Polgár
[Abstract]
Abstracts
[Back to top]
Recent Progress and Future Directions in
Protein-Protein Docking
David W. Ritchie
This article gives an overview of recent progress in
protein-protein docking and it identifies several directions
for future research. Recent results from the CAPRI blind docking
experiments show that docking algorithms are steadily improving
in both reliability and accuracy. Current docking algorithms
employ a range of efficient search and scoring strategies,
including e.g. fast Fourier transform correlations, geometric
hashing, and Monte Carlo techniques. These approaches can
often produce a relatively small list of up to a few thousand
orientations, amongst which a near-native binding mode is
often observed. However, despite the use of improved scoring
functions which typically include models of desolvation, hydrophobicity,
and electrostatics, current algorithms still have difficulty
in identifying the correct solution from the list of false
positives, or decoys. Nonetheless, significant progress is
being made through better use of bioinformatics, biochemical,
and biophysical information such as e.g. sequence conservation
analysis, protein interaction databases, alanine scanning,
and NMR residual dipolar coupling restraints to help identify
key binding residues. Promising new approaches to incorporate
models of protein flexibility during docking are being developed,
including the use of molecular dynamics snapshots, rotameric
and off-rotamer searches, internal coordinate mechanics, and
principal component analysis based techniques. Some investigators
now use explicit solvent models in their docking protocols.
Many of these approaches can be computationally intensive,
although new silicon chip technologies such as programmable
graphics processor units are beginning to offer competitive
alternatives to conventional high performance computer systems.
As cryo-EM techniques improve apace, docking NMR and X-ray
protein structures into low resolution EM density maps is
helping to bridge the resolution gap between these complementary
techniques. The use of symmetry and fragment assembly constraints
are also helping to make possible docking-based predictions
of large multimeric protein complexes. In the near future,
the closer integration of docking algorithms with protein
interface prediction software, structural databases, and sequence
analysis techniques should help produce better predictions
of protein interaction networks and more accurate structural
models of the fundamental molecular interactions within the
cell.
[Back to top]
Activation, Exposure and Penetration of Virally Encoded, Membrane-Active
Polypeptides During Non-Enveloped Virus Entry
Manidipa Banerjee and John E. Johnson
Host cell entry by influenza and other enveloped viruses
is well characterized, however, the manner in which non-enveloped
viruses deliver their genome across host cell membranes in
the absence of membrane fusion remains unresolved. The discovery
of short, membrane altering, amphipathic or hydrophobic sequences
in several non-enveloped virus capsid proteins such as the
γ (gamma)
peptide of nodaviruses and tetraviruses, VP4 and the N-terminal
region of VP1 of picornaviruses, μ1N
of reoviruses, and protein VI of adenoviruses suggests that
these small peptides facilitate breaching of the host membrane
and the delivery of the viral genome into the host cell. In
spite of conspicuous differences in entry among non-enveloped
virions, the short stretches of membrane active regions are
associated with similar, entry-related events including: I)
proteolytic cleavage of a precursor capsid protein resulting
in increased dynamic character and/or accessibility of these
peptides; II) structural changes in the virus capsid triggered
by receptor binding and/or low pH in entry compartments, resulting
in peptide exposure; III) externalized peptides interact with
host membranes and disrupt them, facilitating delivery of
the viral genome inside the host cell. Here we discuss the
membrane alteration activity in non-enveloped viruses with
reference to the γ
peptide of nodaviruses. Virtually all of the characteristics
of γ
are shared by analogous peptides in other non-enveloped viruses,
making it a simple prototype for comparative purposes.
[Back to top]
Proteins As Networks: Usefulness of Graph Theory in Protein
Science
Arun Krishnan, Joseph P. Zbilut, Masaru Tomita and Alessandro
Giuliani
The network paradigm is based on the derivation of emerging
properties of studied systems by their representation as oriented
graphs: any system is traced back to a set of nodes (its constituent
elements) linked by edges (arcs) correspondent to the relations
existing between the nodes. This allows for a straightforward
quantitative formalization of systems by means of the computation
of mathematical descriptors of such graphs (graph theory).
The network paradigm is particularly useful when it is clear
which elements of the modelled system must play the role of
nodes and arcs respectively, and when topological constraints
have a major role with respect to kinetic ones. In this review
we demonstrate how nodes and arcs of protein topology are
characterized at different levels of definition:
1. Recurrence matrix of hydrophobicity patterns along the
sequence
2. Contact matrix of alpha carbons of 3D structures
3. Correlation matrix of motions of different portion of the
molecule in molecular dynamics.
These three conditions represent different but potentially
correlated reticular systems that can be profitably analysed
by means of network analysis tools.
[Back to top]
Lantibiotic Immunity
Lorraine A. Draper, R. Paul Ross, Colin Hill and Paul
D. Cotter
Lantibiotics are a diverse family of bacterially synthesized
antimicrobial peptides produced by gram-positive bacteria.
They usually have a broad spectrum of targets, often including
closely related strains. The production of lantibiotics must
thus be coupled with a mechanism by which the producing strain
can protect itself from the lethal action of its own antimicrobial
compound. This mechanism is referred to as immunity. Lantibiotic
immunity is usually provided by one, or both, of two methods
i.e. by a specific immunity peptide (designated LanI) and/or
a specialised ABC transporter system (designated LanFE(G)).
Significantly, although the specific immunity peptides function
in a similar manner, there is very little homology between
them. This is reflected in the specific nature of the immunity
provided. Finally, of equal importance is the manner in which
these immunity determinants are regulated such that their
expression is timed to occur with, or immediately prior to,
lantibiotic production to ensure successful self-protection.
[Back to top]
NMR of Membrane-Associated Peptides and Proteins
Guangshun Wang
In living cells, membrane proteins are essential to signal
transduction, nutrient use, and energy exchange between the
cell and environment. Due to challenges in protein expression,
purification and crystallization, deposition of membrane protein
structures in the Protein Data Bank lags far behind existing
structures for soluble proteins. This review describes recent
advances in solution NMR allowing the study of a select set
of peripheral and integral membrane proteins. Surface-binding
proteins discussed include amphitropic proteins, antimicrobial
and anticancer peptides, the HIV-1 gp41 peptides, human α
-synuclein and apolipoproteins. Also discussed are transmembrane
proteins including bacterial outer membrane β-barrel
proteins and oligomeric α-helical
proteins. These structural studies are possible due to solubilization
of the proteins in membrane-mimetic constructs such as detergent
micelles and bicelles. In addition to protein dynamics, protein-lipid
interactions such as those between arginines and phosphatidylglycerols
have been detected directly by NMR. These examples illustrate
the unique role solution NMR spectroscopy plays in structural
biology of membrane proteins.
[Back to top]
Homology-Free Prediction of Functional Class of Proteins and
Peptides by Support Vector Machines
F. Zhu, L.Y. Han, X. Chen, H.H. Lin, S. Ong, B. Xie, H.L.
Zhang and Y.Z. Chen
Protein and peptide sequences contain clues for functional
prediction. A challenge is to predict sequences that show
low or no homology to proteins or peptides of known function.
A machine learning method, support vector machines (SVM),
has recently been explored for predicting functional class
of proteins and peptides from sequence-derived properties
irrespective of sequence similarity, which has shown impressive
performance for predicting a wide range of protein and peptide
classes including certain low- and non- homologous sequences.
This method serves as a new and valuable addition to complement
the extensively-used alignment-based, clustering-based, and
structure-based functional prediction methods. This article
evaluates the strategies, current progresses, reported prediction
performances, available software tools, and underlying difficulties
in using SVM for predicting the functional class of proteins
and peptides.
[Back to top]
Structure, Function and Biological Relevance of Prolyl Oligopeptidase
Zoltán Szeltner and László Polgár
A group of serine peptidases, the prolyl oligopeptidase
family, cannot hydrolyze proteins and peptides containing
more than 30 residues. The crystal structure of prolyl oligopeptidase
(POP) has shown that the enzyme is composed of a peptidase
domain with an α
/ β
hydrolase fold and a seven-bladed β-propeller
domain. This domain covers the catalytic triad and excludes
large, structured peptides from the active site. The mechanism
of substrate selection has been reviewed, along with the binding
mode of the substrate and the catalytic mechanism, which differ
from that of the classical serine peptidases in several features.
POP is essentially a cytosolic enzyme and has been shown to
be involved in a number of biological processes, but its precise
function is still unknown. Many reports addressed experimentally
the possible role of POP in cognitive and psychiatric processes,
its involvement in the inositol phosphate signaling pathway,
and its ability to metabolize bioactive peptides. Inhibitors
were designed to reveal the cellular functions of POP and
to treat neurological disorders. Other studies concerned the
cellular localization of POP, its presumed interaction with
the cytoskeletal elements, and its involvement in peptide/protein
transport/secretion processes. The possible role of POP in
Alzheimer disease is an intriguing issue, which is still debated.
Recently, recombinant bacterial POPs have been investigated
as potential therapeutics for celiac sprue, an autoimmune
disease of small intestine caused by the intake of gluten
proteins.
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