762 research outputs found
Loop-closure principles in protein folding
Simple theoretical concepts and models have been helpful to understand the
folding rates and routes of single-domain proteins. As reviewed in this
article, a physical principle that appears to underly these models is loop
closure.Comment: 27 pages, 5 figures; to appear in Archives of Biochemistry and
Biophysic
Loop-closure events during protein folding: Rationalizing the shape of Phi-value distributions
In the past years, the folding kinetics of many small single-domain proteins
has been characterized by mutational Phi-value analysis. In this article, a
simple, essentially parameter-free model is introduced which derives folding
routes from native structures by minimizing the entropic loop-closure cost
during folding. The model predicts characteristic folding sequences of
structural elements such as helices and beta-strand pairings. Based on few
simple rules, the kinetic impact of these structural elements is estimated from
the routes and compared to average experimental Phi-values for the helices and
strands of 15 small, well-characterized proteins. The comparison leads on
average to a correlation coefficient of 0.62 for all proteins with polarized
Phi-value distributions, and 0.74 if distributions with negative average
Phi-values are excluded. The diffuse Phi-value distributions of the remaining
proteins are reproduced correctly. The model shows that Phi-value
distributions, averaged over secondary structural elements, can often be traced
back to entropic loop-closure events, but also indicates energetic preferences
in the case of a few proteins governed by parallel folding processes.Comment: 24 pages, 3 figures, 2 tables; to appear in "Proteins: Structure,
Function, and Bioinformatics
Conformational selection in protein binding and function
Protein binding and function often involves conformational changes. Advanced
NMR experiments indicate that these conformational changes can occur in the
absence of ligand molecules (or with bound ligands), and that the ligands may
'select' protein conformations for binding (or unbinding). In this review, we
argue that this conformational selection requires transition times for ligand
binding and unbinding that are small compared to the dwell times of proteins in
different conformations, which is plausible for small ligand molecules. Such a
separation of timescales leads to a decoupling and temporal ordering of
binding/unbinding events and conformational changes. We propose that
conformational-selection and induced-change processes (such as induced fit) are
two sides of the same coin, because the temporal ordering is reversed in
binding and unbinding direction. Conformational-selection processes can be
characterized by a conformational excitation that occurs prior to a binding or
unbinding event, while induced-change processes exhibit a characteristic
conformational relaxation that occurs after a binding or unbinding event. We
discuss how the ordering of events can be determined from relaxation rates and
effective on- and off-rates determined in mixing experiments, and from the
conformational exchange rates measured in advanced NMR or single-molecule FRET
experiments. For larger ligand molecules such as peptides, conformational
changes and binding events can be intricately coupled and exhibit aspects of
conformational-selection and induced-change processes in both binding and
unbinding direction.Comment: review article; 10 pages, 4 figures, Protein Sci. 201
Membrane adhesion and domain formation
We review theoretical results for the adhesion-induced phase behavior of
biomembranes. The focus is on models in which the membranes are represented as
discretized elastic sheets with embedded adhesion molecules. We present several
mechanism that lead to the formation of domains during adhesion, and discuss
the time-dependent evolution of domain patterns obtained in Monte-Carlo
simulations. The simulated pattern dynamics has striking similarities to the
pattern evolution observed during T cell adhesion.Comment: 68 pages, 29 figure
How conformational changes can affect catalysis, inhibition and drug resistance of enzymes with induced-fit binding mechanism such as the HIV-1 protease
A central question is how the conformational changes of proteins affect their
function and the inhibition of this function by drug molecules. Many enzymes
change from an open to a closed conformation upon binding of substrate or
inhibitor molecules. These conformational changes have been suggested to follow
an induced-fit mechanism in which the molecules first bind in the open
conformation in those cases where binding in the closed conformation appears to
be sterically obstructed such as for the HIV-1 protease. In this article, we
present a general model for the catalysis and inhibition of enzymes with
induced-fit binding mechanism. We derive general expressions that specify how
the overall catalytic rate of the enzymes depends on the rates for binding, for
the conformational changes, and for the chemical reaction. Based on these
expressions, we analyze the effect of mutations that mainly shift the
conformational equilibrium on catalysis and inhibition. If the overall
catalytic rate is limited by product unbinding, we find that mutations that
destabilize the closed conformation relative to the open conformation increase
the catalytic rate in the presence of inhibitors by a factor exp(ddG/RT) where
ddG is the mutation-induced shift of the free-energy difference between the
conformations. This increase in the catalytic rate due to changes in the
conformational equilibrium is independent of the inhibitor molecule and, thus,
may help to understand how non-active-site mutations can contribute to the
multi-drug-resistance that has been observed for the HIV-1 protease. A
comparison to experimental data for the non-active-site mutation L90M of the
HIV-1 protease indicates that the mutation slightly destabilizes the closed
conformation of the enzyme.Comment: 9 pages, 2 figures, 3 tables; to appear in "BBA Proteins and
Proteomics" as part of a special issue with the title "The emerging dynamic
view of proteins: Protein plasticity in allostery, evolution and
self-assembly.
Adhesion-induced phase separation of multiple species of membrane junctions
A theory is presented for the membrane junction separation induced by the
adhesion between two biomimetic membranes that contain two different types of
anchored junctions (receptor/ligand complexes). The analysis shows that several
mechanisms contribute to the membrane junction separation. These mechanisms
include (i) the height difference between type-1 and type-2 junctions is the
main factor which drives the junction separation, (ii) when type-1 and type-2
junctions have different rigidities against stretch and compression, the
``softer'' junctions are the ``favored'' species, and the aggregation of the
softer junction can occur, (iii) the elasticity of the membranes mediates a
non-local interaction between the junctions, (iv) the thermally activated shape
fluctuations of the membranes also contribute to the junction separation by
inducing another non-local interaction between the junctions and renormalizing
the binding energy of the junctions. The combined effect of these mechanisms is
that when junction separation occurs, the system separates into two domains
with different relative and total junction densities.Comment: 23 pages, 6 figure
Transition States in Protein Folding Kinetics: The Structural Interpretation of Phi-values
Phi-values are experimental measures of the effects of mutations on the
folding kinetics of a protein. A central question is which structural
information Phi-values contain about the transition state of folding.
Traditionally, a Phi-value is interpreted as the 'nativeness' of a mutated
residue in the transition state. However, this interpretation is often
problematic because it assumes a linear relation between the nativeness of the
residue and its free-energy contribution. We present here a better structural
interpretation of Phi-values for mutations within a given helix. Our
interpretation is based on a simple physical model that distinguishes between
secondary and tertiary free-energy contributions of helical residues. From a
linear fit of our model to the experimental data, we obtain two structural
parameters: the extent of helix formation in the transition state, and the
nativeness of tertiary interactions in the transition state. We apply our model
to all proteins with well-characterized helices for which more than 10
Phi-values are available: protein A, CI2, and protein L. The model captures
nonclassical Phi-values 1 in these helices, and explains how different
mutations at a given site can lead to different Phi-values.Comment: 26 pages, 7 figures, 5 table
A simple measure of native-state topology and chain connectivity predicts the folding rates of two-state proteins with and without crosslinks
The folding rates of two-state proteins have been found to correlate with
simple measures of native-state topology. The most prominent among these
measures is the relative contact order (CO), which is the average CO or
'localness' of all contacts in the native protein structure, divided by the
chain length. Here, we test whether such measures can be generalized to capture
the effect of chain crosslinks on the folding rate. Crosslinks change the chain
connectivity and therefore also the localness of some of the the native
contacts. These changes in localness can be taken into account by the
graph-theoretical concept of effective contact order (ECO). The relative ECO,
however, the natural extension of the relative CO for proteins with crosslinks,
overestimates the changes in the folding rates caused by crosslinks. We suggest
here a novel measure of native-state topology, the relative logCO, and its
natural extension, the relative logECO. The relative logCO is the average value
for the logarithm of the CO of all contacts, divided by the logarithm of the
chain length. The relative log(E)CO reproduces the folding rates of a set of 26
two-state proteins without crosslinks with essentially the same high
correlation coefficient as the relative CO. In addition, it also captures the
folding rates of 8 two-state proteins with crosslinks.Comment: 13 pages, 2 tables, and 2 figure
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