Proteins: Structure, Function and Bioinformatics
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Exploiting sequence and structure homologs to identify protein–protein binding sites Abstract A rapid increase in the number of experimentally derived three‐dimensional structures provides an opportunity to better understand and subsequently predict protein–protein interactions. In this study, structurally conserved residues were derived from multiple structure alignments of the individual components of known complexes and the assigned conservation score was weighted based on the crystallographic B factor to account for the structural flexibility that will result in a poor alignment. Sequence profile and accessible surface area information was then combined with the conservation score to predict protein–protein binding sites using a Support Vector Machine (SVM). The incorporation of the conservation score significantly improved the performance of the SVM. About 52% of the binding sites were precisely predicted (greater than 70% of the residues in the site were identified); 77% of the binding sites were correctly predicted (greater than 50% of the residues in the site were identified), and 21% of the binding sites were partially covered by the predicted residues (some residues were identified). The results support the hypothesis that in many cases protein interfaces require some residues to provide rigidity to minimize the entropic cost upon complex formation. Proteins 2006. © 2005 Wiley‐Liss, Inc.
Proteins: Structure, Function and Bioinformatics - Tập 62 Số 3 - Trang 630-640 - 2006
Shape complementarity of protein–protein complexes at multiple resolutions Abstract Biological complexes typically exhibit intermolecular interfaces of high shape complementarity. Many computational docking approaches use this surface complementarity as a guide in the search for predicting the structures of protein–protein complexes. Proteins often undergo conformational changes to create a highly complementary interface when associating. These conformational changes are a major cause of failure for automated docking procedures when predicting binding modes between proteins using their unbound conformations. Low resolution surfaces in which high frequency geometric details are omitted have been used to address this problem. These smoothed, or blurred, surfaces are expected to minimize the differences between free and bound structures, especially those that are due to side chain conformations or small backbone deviations. Despite the fact that this approach has been used in many docking protocols, there has yet to be a systematic study of the effects of such surface smoothing on the shape complementarity of the resulting interfaces. Here we investigate this question by computing shape complementarity of a set of 66 protein–protein complexes represented by multiresolution blurred surfaces. Complexed and unbound structures are available for these protein–protein complexes. They are a subset of complexes from a nonredundant docking benchmark selected for rigidity (i.e. the proteins undergo limited conformational changes between their bound and unbound states). In this work, we construct the surfaces by isocontouring a density map obtained by accumulating the densities of Gaussian functions placed at all atom centers of the molecule. The smoothness or resolution is specified by a Gaussian fall‐off coefficient, termed “blobbyness.” Shape complementarity is quantified using a histogram of the shortest distances between two proteins' surface mesh vertices for both the crystallographic complexes and the complexes built using the protein structures in their unbound conformation. The histograms calculated for the bound complex structures demonstrate that medium resolution smoothing (blobbyness = −0.9) can reproduce about 88% of the shape complementarity of atomic resolution surfaces. Complexes formed from the free component structures show a partial loss of shape complementarity (more overlaps and gaps) with the atomic resolution surfaces. For surfaces smoothed to low resolution (blobbyness = −0.3), we find more consistency of shape complementarity between the complexed and free cases. To further reduce bad contacts without significantly impacting the good contacts we introduce another blurred surface, in which the Gaussian densities of flexible atoms are reduced. From these results we discuss the use of shape complementarity in protein–protein docking. Proteins 2009. © 2008 Wiley‐Liss, Inc.
Proteins: Structure, Function and Bioinformatics - Tập 75 Số 2 - Trang 453-467 - 2009
Cation–π, amino–π, π–π, and H‐bond interactions stabilize antigen–antibody interfaces
Proteins: Structure, Function and Bioinformatics - Tập 82 Số 9 - Trang 1734-1746 - 2014
Comparative analysis of nanobody sequence and structure data Abstract Nanobodies are a class of antigen‐binding protein derived from camelids that achieve comparable binding affinities and specificities to classical antibodies, despite comprising only a single 15 kDa variable domain. Their reduced size makes them an exciting target molecule with which we can explore the molecular code that underpins binding specificity—how is such high specificity achieved? Here, we use a novel dataset of 90 nonredundant, protein‐binding nanobodies with antigen‐bound crystal structures to address this question. To provide a baseline for comparison we construct an analogous set of classical antibodies, allowing us to probe how nanobodies achieve high specificity binding with a dramatically reduced sequence space. Our analysis reveals that nanobodies do not diversify their framework region to compensate for the loss of the VL domain. In addition to the previously reported increase in H3 loop length, we find that nanobodies create diversity by drawing their paratope regions from a significantly larger set of aligned sequence positions, and by exhibiting greater structural variation in their H1 and H2 loops.
Proteins: Structure, Function and Bioinformatics - Tập 86 Số 7 - Trang 697-706 - 2018
Amphipathic helix motif: Classes and properties
Proteins: Structure, Function and Bioinformatics - Tập 8 Số 2 - Trang 103-117 - 1990
Structure of Met‐enkephalin in explicit aqueous solution using replica exchange molecular dynamics Abstract Replica exchange molecular dynamics (MD) simulations of Met‐enkephalin in explicit solvent reveal helical and nonhelical structures. Four predominant structures of Met‐enkephalin are sampled with comparable probabilities (two helical and two nonhelical). The energy barriers between these configurations are low, suggesting that Met‐enkephalin switches easily between configurations. This is consistent with the requirement that Met‐enkephalin be sufficiently flexible to bind to several different receptors. Replica exchange simulations of 32 ns are shown to sample approximately five times more configurational space than constant temperature MD simulations of the same duration. The energy landscape for the replica exchange simulation is presented. A detailed study of replica trajectories demonstrates that the significant increases in temperature provided by the replica exchange technique enable transitions from nonhelical to helical structures that would otherwise be prevented by kinetic trapping. Met‐enkephalin (Type Entrez Proteins; Value A61445; Service Entrez Proteins) Proteins 2002;46:225–234. Published 2001 Wiley‐Liss, Inc.
Proteins: Structure, Function and Bioinformatics - Tập 46 Số 2 - Trang 225-234 - 2002
The architecture of the binding site in redox protein complexes: Implications for fast dissociation Abstract Interprotein electron transfer is characterized by protein interactions on the millisecond time scale. Such transient encounters are ensured by extremely high rates of complex dissociation. Computational analysis of the available crystal structures of redox protein complexes reveals features of the binding site that favor fast dissociation. In particular, the complex interface is shown to have low geometric complementarity and poor packing. These features are consistent with the necessity for fast dissociation since the absence of close packing facilitates solvation of the interface and disruption of the complex. Proteins 2004;55:000–000. © 2004 Wiley‐Liss, Inc.
Proteins: Structure, Function and Bioinformatics - Tập 55 Số 3 - Trang 603-612 - 2004
Host‐guest scale of left‐handed polyproline II helix formation Abstract Despite the clear importance of the left‐handed polyproline II (PPII) helical conformation in many physiologically important processes as well as its potential significance in protein unfolded states, little is known about the physical determinants of this conformation. We present here a scale of relative PPII helix‐forming propensities measured for all residues, except tyrosine and tryptophan, in a proline‐based host peptide system. Proline has the highest measured propensity in this system, a result of strong steric interactions that occur between adjacent prolyl rings. The other measured propensities are consistent with backbone solvation being an important component in PPII helix formation. Side chain to backbone hydrogen bonding may also play a role in stabilizing this conformation. The PPII helix‐forming propensity scale will prove useful in future studies of the conformational properties of proline‐rich sequences as well as provide insights into the prevalence of PPII helices in protein unfolded states. Proteins 2003. © 2003 Wiley‐Liss, Inc.
Proteins: Structure, Function and Bioinformatics - Tập 53 Số 1 - Trang 68-75 - 2003
Unfolded state of polyalanine is a segmented polyproline II helix Abstract Definition of the unfolded state of proteins is essential for understanding their stability and folding on biological timescales. Here, we find that under near physiological conditions the configurational ensemble of the unfolded state of the simplest protein structure, polyalanine α‐helix, cannot be described by the commonly used Flory random coil model, in which configurational probabilities are derived from conformational preferences of individual residues. We utilize novel effectively ergodic sampling algorithms in the presence of explicit aqueous solvation, and observe water‐mediated formation of polyproline II helical (PII ) structure in the natively unfolded state of polyalanine, and its facilitation of α‐helix formation in longer peptides. The segmented PII helical coil preorganizes the unfolded state ensemble for folding pathway entry by reducing the conformational space available to the diffusive search. Thus, as much as half of the folding search in polyalanine is accomplished by preorganization of the unfolded state. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Proteins: Structure, Function and Bioinformatics - Tập 55 Số 3 - Trang 493-501 - 2004
A tetrapeptide‐based method for polyproline II‐type secondary structure prediction Abstract We describe a new method for polyproline II‐type (PPII) secondary structure prediction based on tetrapeptide conformation properties using data obtained from all globular proteins in the Protein Data Bank (PDB). This is the first method for PPII prediction with a relatively high level of accuracy (∼60%). Our method uses only frequencies of different conformations among oligopeptides without any additional parameters. We also attempted to predict α‐helices and β‐strands using the same approach. We find that the application of our method reveals interrelation between sequence and structure even for very short oligopeptides (tetrapeptides). Proteins 2005. © 2005 Wiley‐Liss, Inc.
Proteins: Structure, Function and Bioinformatics - Tập 61 Số 4 - Trang 763-768 - 2005
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