			Home About us Contact

Protein Interfaces (protein + interface)

Distribution by Scientific Domains

Chemistry	55%

Selected Abstracts

Atomic Interactions and Profile of Small Molecules Disrupting Protein,Protein Interfaces: the TIMBAL Database

CHEMICAL BIOLOGY & DRUG DESIGN, Issue 5 2009
Alícia P. Higueruelo
Growing evidence of the possibility of modulating protein,protein interactions with small molecules is opening the door to new approaches and concepts in drug discovery. In this paper, we describe the creation of TIMBAL, a hand-curated database holding an up to date collection of small molecules inhibiting multi-protein complexes. This database has been analysed and profiled in terms of molecular properties. Protein,protein modulators tend to be large lipophilic molecules with few hydrogen bond features. An analysis of TIMBAL's intersection with other structural databases, including CREDO (protein,small molecule from the PDB) and PICCOLO (protein,protein from the PDB) reveals that TIMBAL molecules tend to form mainly hydrophobic interactions with only a few hydrogen bonding contacts. With respect to potency, TIMBAL molecules are slightly less efficient than an average medicinal chemistry hit or lead. The database provides a resource that will allow further insights into the types of molecules favoured by protein interfaces and provide a background to continuing work in this area. Access at http://www-cryst.bioc.cam.ac.uk/timbal [source]

Evaluation of Endothelial Cell Adhesion onto Different Protein/Gold Electrodes by EIS

MACROMOLECULAR BIOSCIENCE, Issue 5 2007
Amira Bouafsoun
Abstract To study cell attachment to biomaterials, several proteins such as fibronectin, collagen IV, heparin, immunoglobulin G, and albumin have been deposited onto polystyrene adsorbed on a self-assembled monolayer (silane or thiol) on glass or gold, respectively. The different steps of this multilayer assembly have been characterized by electrochemical impedance spectroscopy (EIS). These data are compared to those of adhesion rate, viability percentage, and cytoskeleton labeling for a better understanding of the cell adhesion process to each protein. All the proteins are endothelial cell adhering biomolecules but not with the same features. A linear relationship has been established between adhesion rate and resistance of the endothelial cell/protein interface for all negatively charged proteins. [source]

Stoichiometry of lipid interactions with transmembrane proteins,Deduced from the 3D structures

PROTEIN SCIENCE, Issue 5 2006
Tibor Páli
Abstract The stoichiometry of the first shell of lipids interacting with a transmembrane protein is defined operationally by the population of spin-labeled lipid chains whose motion is restricted directly by the protein. Interaction stoichiometries have been determined experimentally for a wide range of ,-helical integral membrane proteins by using spin-label ESR spectroscopy. Here, we determine the spatially defined number of first-shell lipids at the hydrophobic perimeter of integral membrane proteins whose 3D structure has been determined by X-ray crystallography and lipid,protein interactions characterized by spin-labeling. Molecular modeling is used to build a single shell of lipids surrounding transmembrane structures derived from the PDB. Constrained energy optimization of the protein,lipid assemblies is performed by molecular mechanics. For relatively small proteins (up to 7,12 transmembrane helices), the geometrical first shell corresponds to that defined experimentally by perturbation of the lipid-chain dynamics. For larger, multi-subunit ,-helical proteins, the lipids perturbed directly by the protein may either exceed or be less in number than those that can be accommodated at the intramembranous perimeter. In these latter cases, the motionally restricted spin-labeled lipids can be augmented by intercalation, or can correspond to a specific subpopulation at the protein interface, respectively. For monomeric ,-barrel proteins, the geometrical lipid stoichiometry corresponds to that determined from lipid mobility for a 22-stranded barrel, but fewer lipids are motionally restricted than can be accommodated around an eight-stranded barrel. Deviations from the geometrical first shell, in the ,-barrel case, are for the smaller protein with a highly curved barrel. [source]

WATGEN: An algorithm for modeling water networks at protein,protein interfaces

JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 14 2007
Huynh-Hoa Bui
Abstract Water molecules at protein,protein interfaces contribute to the close packing of atoms and ensure complementarity between the protein surfaces, as well as mediating polar interactions. Therefore, modeling of interface water is of importance in understanding the structural basis of biomolecular association. We present an algorithm, WATGEN, which predicts locations for water molecules at a protein,protein or protein,peptide interface, given the atomic coordinates of the protein and peptide. A key element of the WATGEN algorithm is the prediction of water sites that can form multiple hydrogen bonds that bridge the binding interface. Trial calculations were performed on water networks predicted by WATGEN at 126 protein,peptide interfaces (X-ray resolutions , 2.0 Å), using different criteria for water placement. The energies of the predicted water networks were evaluated in AMBER8 and used in the choice of parameters for WATGEN. The 126 interfaces include 1264 experimentally determined bridging water sites, and the WATGEN algorithm predicts 72 and 88% of these sites within 1.5 and 2.0 Å, respectively. The predicted number of water molecules at each interface was much higher than the number of water molecules identified experimentally. Therefore, random placement of the same number of water molecules as that predicted at each interface was performed as a control, and resulted in only 22 and 40% of water sites placed within 1.5 and 2.0 Å of experimental sites, respectively. Based on these data, we conclude that WATGEN can accurately predict the location of water molecules at a protein,peptide interface, and this may be of value for understanding the energetics and specificity of biomolecular association. © 2007 Wiley Periodicals, Inc. J Comput Chem, 2007 [source]

Exploring functional roles of multibinding protein interfaces

PROTEIN SCIENCE, Issue 8 2009
Manoj Tyagi
Abstract Cellular processes are highly interconnected and many proteins are shared in different pathways. Some of these shared proteins or protein families may interact with diverse partners using the same interface regions; such multibinding proteins are the subject of our study. The main goal of our study is to attempt to decipher the mechanisms of specific molecular recognition of multiple diverse partners by promiscuous protein regions. To address this, we attempt to analyze the physicochemical properties of multibinding interfaces and highlight the major mechanisms of functional switches realized through multibinding. We find that only 5% of protein families in the structure database have multibinding interfaces, and multibinding interfaces do not show any higher sequence conservation compared with the background interface sites. We highlight several important functional mechanisms utilized by multibinding families. (a) Overlap between different functional pathways can be prevented by the switches involving nearby residues of the same interfacial region. (b) Interfaces can be reused in pathways where the substrate should be passed from one protein to another sequentially. (c) The same protein family can develop different specificities toward different binding partners reusing the same interface; and finally, (d) inhibitors can attach to substrate binding sites as substrate mimicry and thereby prevent substrate binding. [source]

A Targeted Releasable Affinity Probe (TRAP) for In Vivo Photocrosslinking

CHEMBIOCHEM, Issue 9 2009
Ping Yan Dr.
Abstract A protein TRAP: The in vivo photocrosslinking of TRAP after its intracellular targeting to a binding sequence on the bait protein stabilizes protein interactions. Because the crosslinker is releasable, simple mass spectrometry can be used to identify the protein binding sites after purification. Protein crosslinking, especially coupled to mass-spectrometric identification, is increasingly used to determine protein binding partners and protein,protein interfaces for isolated protein complexes. The modification of crosslinkers to permit their targeted use in living cells is of considerable importance for studying protein-interaction networks, which are commonly modulated through weak interactions that are formed transiently to permit rapid cellular response to environmental changes. We have therefore synthesized a targeted and releasable affinity probe (TRAP) consisting of a biarsenical fluorescein linked to benzophenone that binds to a tetracysteine sequence in a protein engineered for specific labeling. Here, the utility of TRAP for capturing protein binding partners upon photoactivation of the benzophenone moiety has been demonstrated in living bacteria and mammalian cells. In addition, ligand exchange of the arsenic,sulfur bonds between TRAP and the tetracysteine sequence to added dithiols results in fluorophore transfer to the crosslinked binding partner. In isolated protein complexes, this release from the original binding site permits the identification of the proximal binding interface through mass spectrometric fragmentation and computational sequence identification. [source]

Probing the ,-Helical Structural Stability of Stapled p53 Peptides: Molecular Dynamics Simulations and Analysis

CHEMICAL BIOLOGY & DRUG DESIGN, Issue 4 2010
Zuojun Guo
Reactivation of the p53 cell apoptosis pathway through inhibition of the p53-hDM2 interaction is a viable approach to suppress tumor growth in many human cancers and stabilization of the helical structure of synthetic p53 analogs via a hydrocarbon cross-link (staple) has been found to lead to increased potency and inhibition of protein,protein binding (J. Am. Chem. Soc. 129: 5298). However, details of the structure and dynamic stability of the stapled peptides are not well understood. Here, we use extensive all-atom molecular dynamics simulations to study a series of stapled ,-helical peptides over a range of temperatures in solution. The peptides are found to exhibit substantial variations in predicted ,-helical propensities that are in good agreement with the experimental observations. In addition, we find significant variation in local structural flexibility of the peptides with the position of the linker, which appears to be more closely related to the observed differences in activity than the absolute ,-helical stability. These simulations provide new insights into the design of ,-helical stapled peptides and the development of potent inhibitors of ,-helical protein,protein interfaces. [source]