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Hydrophobic pulses predict transmembrane helix irregularities and channel transmembrane units

BMC BIOINFORMATICS 2011年第1期12卷 1-10页

作者： Paulet, Damien Claustres, Mireille Beroud, Christophe Univ Montpellier I Montpellier France INSERM U827 Montpellier France Hop Arnaud de Villeneuve Lab Genet Mol CHU Montpellier Montpellier France

Background: Few high-resolution structures of integral membranes proteins are available, as crystallization of such proteins needs yet to overcome too many technical limitations. Nevertheless, prediction of their transmembrane (TM) structure by bioinformatics tools provides interesting insights on the topology of these proteins. Methods: We describe here how to extract new information from the analysis of hydrophobicity variations or hydrophobic pulses (HPulses) in the sequence of integral membrane proteins using the Hydrophobic Pulse Predictor, a new tool we developed for this purpose. To analyze the primary sequence of 70 integral membrane proteins we defined two levels of analysis: G1-HPulses for sliding windows of n = 2 to 6 and G2-HPulses for sliding windows of n = 12 to 16. Results: The G2-HPulse analysis of 541 transmembrane helices allowed the definition of the new concept of transmembrane unit (TMU) that groups together transmembrane helices and segments with potential adjacent structures. In addition, the G1-HPulse analysis identified helix irregularities that corresponded to kinks, partial helices or unannotated structural events. These irregularities could represent key dynamic elements that are alternatively activated depending on the channel status as illustrated by the crystal structures of the lactose permease in different conformations. Conclusions: Our results open a new way in the understanding of transmembrane secondary structures: hydrophobicity through hydrophobic pulses strongly impacts on such embedded structures and is not confined to define the transmembrane status of amino acids.

关键词： Integral Membrane protein Transmembrane Helix protein data bank file Structural Irregularity Lactose Permease

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Fast automated placement of polar hydrogen atoms in protein-ligand complexes

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JOURNAL OF CHEMINFORMATICS 2009年第1期1卷 13-13页

作者： Lippert, Tobias Rarey, Matthias Ctr Bioinformat D-20146 Hamburg Germany

Background: Hydrogen bonds play a major role in the stabilization of protein-ligand complexes. The ability of a functional group to form them depends on the position of its hydrogen atoms. An accurate knowledge of the positions of hydrogen atoms in proteins is therefore important to correctly identify hydrogen bonds and their properties. The high mobility of hydrogen atoms introduces several degrees of freedom: Tautomeric states, where a hydrogen atom alters its binding partner, torsional changes where the position of the hydrogen atom is rotated around the last heavy-atom bond in a residue, and protonation states, where the number of hydrogen atoms at a functional group may change. Also, side-chain flips in glutamine and asparagine and histidine residues, which are common crystallographic ambiguities must be identified before structure-based calculations can be conducted. Results: We have implemented a method to determine the most probable hydrogen atom positions in a given protein-ligand complex. Optimality of hydrogen bond geometries is determined by an empirical scoring function which is used in molecular docking. This allows to evaluate protein-ligand interactions with an established model. Also, our method allows to resolve common crystallographic ambiguities such as as flipped amide groups and histidine residues. To ensure high speed, we make use of a dynamic programming approach. Conclusion: Our results were checked against selected high-resolution structures from an external dataset, for which the positions of the hydrogen atoms have been validated manually. The quality of our results is comparable to that of other programs, with the advantage of being fast enough to be applied on-the-fly for interactive usage or during score evaluation.

关键词： protein data bank Hydrogen Bond Network Dynamic Programming Approach Interaction Score protein data bank file

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Predicting DNA-binding locations and orientation on proteins using knowledge-based learning of geometric properties

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PROTEOME SCIENCE 2011年第1-Sup期9卷 S11-S11页

作者： Wang, Chien-Chih Chen, Chien-Yu Natl Taiwan Univ Dept Bioind Mechatron Engn Taipei 106 Taiwan Natl Taiwan Univ Dept Comp Sci & Informat Engn Taipei 106 Taiwan

Background: DNA-binding proteins perform their functions through specific or non-specific sequence recognition. Although many sequence-or structure-based approaches have been proposed to identify DNA-binding residues on proteins or protein-binding sites on DNA sequences with satisfied performance, it remains a challenging task to unveil the exact mechanism of protein-DNA interactions without crystal complex structures. Without information from complexes, the linkages between DNA-binding proteins and their binding sites on DNA are still missing. Methods: While it is still difficult to acquire co-crystallized structures in an efficient way, this study proposes a knowledge-based learning method to effectively predict DNA orientation and base locations around the protein's DNA-binding sites when given a protein structure. First, the functionally important residues of a query protein are predicted by a sequential pattern mining tool. After that, surface residues falling in the predicted functional regions are determined based on the given structure. These residues are then clustered based on their spatial coordinates and the resultant clusters are ranked by a proposed DNA-binding propensity function. Clusters with high DNA-binding propensities are treated as DNA-binding units (DBUs) and each DBU is analyzed by principal component analysis (PCA) to predict potential orientation of DNA grooves. More specifically, the proposed method is developed to predict the direction of the tangent line to the helix curve of the DNA groove where a DBU is going to bind. Results: This paper proposes a knowledge-based learning procedure to determine the spatial location of the DNA groove with respect to the query protein structure by considering geometric propensity between protein side chains and DNA bases. The 11 test cases used in this study reveal that the location and orientation of the DNA groove around a selected DBU can be predicted with satisfied errors. Conclusions: This study pr

关键词： Root Mean Square Deviation Query protein Amino Acid Type Sequential Pattern Mining protein data bank file

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Inhibition of the NEMO/IKKβ association complex formation, a novel mechanism associated with the NF-κB activation suppression by Withania somnifera's key metabolite withaferin A

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BMC GENOMICS 2010年第4-Sup期11卷 S25-S25页

作者： Grover, Abhinav Shandilya, Ashutosh Punetha, Ankita Bisaria, Virendra S. Sundar, Durai Indian Inst Technol Dept Biochem Engn & Biotechnol New Delhi 110016 India Indian Inst Technol Supercomp Facil Bioinformat & Computat Biol New Delhi 110016 India

Background: Nuclear Factor kappa B (NF-kappa B) is a transcription factor involved in the regulation of cell signaling responses and is a key regulator of cellular processes involved in the immune response, differentiation, cell proliferation, and apoptosis. The constitutive activation of NF-kappa B contributes to multiple cellular outcomes and pathophysiological conditions such as rheumatoid arthritis, asthma, inflammatory bowel disease, AIDS and cancer. Thus there lies a huge therapeutic potential beneath inhibition of NF-kappa B signalling pathway for reducing these chronic ailments. Withania somnifera, a reputed herb in ayurvedic medicine, comprises a large number of steroidal lactones known as withanolides which show plethora of pharmacological activities like anti-inflammatory, antitumor, antibacterial, antioxidant, anticonvulsive, and immunosuppressive. Though a few studies have been reported depicting the effect of WA (withaferin A) on suppression of NF-kappa B activation, the mechanism behind this is still eluding the researchers. The study conducted here is an attempt to explore NF-kappa B signalling pathway modulating capability of Withania somnifera's major constituent WA and to elucidate its possible mode of action using molecular docking and molecular dynamics simulations studies. Results: Formation of active IKK (I kappa B kinase) complex comprising NEMO (NF-kappa B Essential Modulator) and IKK beta subunits is one of the essential steps for NF-kappa B signalling pathway, non-assembly of which can lead to prevention of the above mentioned vulnerable disorders. As observed from our semi-flexible docking analysis, WA forms strong intermolecular interactions with the NEMO chains thus building steric as well as thermodynamic barriers to the incoming IKK beta subunits, which in turn pave way to naive complex formation capability of NEMO with IKK beta. Docking of WA into active NEMO/IKK beta complex using flexible docking in which key residues of the comple

关键词： Molecular Dynamics Simulation protein data bank Docking Simulation Lamarckian Genetic Algorithm protein data bank file

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In silico modeling of the specific inhibitory potential of thiophene-2,3-dihydro-1,5-benzothiazepine against BChE in the formation of β-amyloid plaques associated with Alzheimer's disease

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THEORETICAL BIOLOGY AND MEDICAL MODELLING 2010年第6期7卷 22-22页

作者： Ul-Haq, Zaheer Khan, Waqasuddin Kalsoom, Saima Ansari, Farzana L. Univ Karachi Int Ctr Chem & Biol Sci Dr Panjwani Ctr Mol Med & Drug Res Karachi 75270 Pakistan Quaid I Azam Univ Dept Chem Islamabad 45320 Pakistan

Background: Alzheimer's disease, known to be associated with the gradual loss of memory, is characterized by low concentration of acetylcholine in the hippocampus and cortex part of the brain. Inhibition of acetylcholinesterase has successfully been used as a drug target to treat Alzheimer's disease but drug resistance shown by butyrylcholinesterase remains a matter of concern in treating Alzheimer's disease. Apart from the many other reasons for Alzheimer's disease, its association with the genesis of fibrils by beta-amyloid plaques is closely related to the increased activity of butyrylcholinesterase. Although few data are available on the inhibition of butyrylcholinesterase, studies have shown that that butyrylcholinesterase is a genetically validated drug target and its selective inhibition reduces the formation of beta-amyloid plaques. Rationale: We previously reported the inhibition of cholinesterases by 2,3-dihydro-1, 5-benzothiazepines, and considered this class of compounds as promising inhibitors for the cure of Alzheimer's disease. One compound from the same series, when substituted with a hydroxy group at C-3 in ring A and 2-thienyl moiety as ring B, showed greater activity against butyrylcholinesterase than to acetylcholinesterase. To provide insight into the binding mode of this compound (Compound A), molecular docking in combination with molecular dynamics simulation of 5000 ps in an explicit solvent system was carried out for both cholinesterases. Conclusion: Molecular docking studies revealed that the potential of Compound A to inhibit cholinesterases was attributable to the cumulative effects of strong hydrogen bonds, cationic-pi, pi-pi interactions and hydrophobic interactions. A comparison of the docking results of Compound A against both cholinesterases showed that amino acid residues in different sub-sites were engaged to stabilize the docked complex. The relatively high affinity of Compound A for butyrylcholinesterase was due to the additional

关键词： protein data bank Root Mean Square Deviation Catalytic Triad Docking Protocol protein data bank file

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Molecular docking studies of dithionitrobenzoic acid and its related compounds to protein disulfide isomerase: computational screening of inhibitors to HIV-1 entry

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BMC BIOINFORMATICS 2008年第12-Sup期9卷 S14-S14页

作者： Gowthaman, Uthaman Jayakanthan, Mannu Sundar, Durai Pondicherry Univ BTISnet Bioinformat Ctr Pondicherry India Indian Inst Technol Dept Biochem Engn & Biotechnol New Delhi 110016 India

Background: Entry of HIV-1 into human lymphoid requires activities of viral envelope glycoproteins gp120 and gp41, and two host-cell proteins, the primary receptor CD4 and a chemokine co-receptor. In addition, a third cell-surface protein called protein disulfide isomerase (PDI) is found to play a major role in HIV-1 entry. PDI is capable of mediating thio-disulfide interchange reactions and could enable the reduction of gp120 disulfide bonds, which triggers the major conformational changes in gp120 and gp41 required for virus entry. In this scenario, inhibition of HIV-1 entry can be brought about by introducing agents that can block thiol-disulfide interchange reaction of cell surface PDI. There have been studies with agents that inhibit PDI activity, but the exact mode of binding remains to be elucidated;this might provide insights to develop new drugs to target PDI. This study attempts to perceive the mode of binding of dithionitrobenzoic acid (DTNB), and its structurally related compounds on PDI enzyme. Results: We performed molecular docking simulation with six different inhibitors (ligand), which includes DTNB, NSC695265, thionitrobenzoic acid, 2-nitro-5-thiocyanobenzoic acid, 2-nitro-5-sulfo-sulfonyl-benzoic acid and NSC517871 into the redox-active site [C37-G38-H39-C40] of the PDI enzyme and the activity was inferred by redox inhibitory models. All ligands showed favorable interactions and most of them seemed to bind to hydrophobic amino acids Ala34, Trp36, Cys37, Cys40, His39, Thr68 and Phe80. The redox inhibitory conformations were energetically and statistically favored and supported the evidence from wet laboratory experiments reported in the literature. Conclusion: We demonstrated that in silico docking experiment can be effectively carried out to recognize the redox inhibitory models of PDI with inhibitor molecules. Interestingly we found that number of docked clusters with each ligand varies in the range of five to eight and conveys that the binding s

关键词： protein data bank Root Mean Square Deviation protein Disulfide Isomerase Docking Simulation protein data bank file

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PDA: an automatic and comprehensive analysis program for protein-DNA complex structures

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BMC GENOMICS 2009年第Sup1期10卷 S13-S13页

作者： Kim, RyangGuk Guo, Jun-tao Univ N Carolina Coll Comp & Informat Dept Bioinformat & Genom Charlotte NC 28223 USA

Background: Knowledge of protein-DNA interactions at the structural-level can provide insights into the mechanisms of protein-DNA recognition and gene regulation. Although over 1400 protein-DNA complex structures have been deposited into protein data bank (PDB), the structural details of protein-DNA interactions are generally not available. In addition, current approaches to comparison of protein-DNA complexes are mainly based on protein sequence similarity while the DNA sequences are not taken into account. With the number of experimentally-determined protein-DNA complex structures increasing, there is a need for an automatic program to analyze the protein-DNA complex structures and to provide comprehensive structural information for the benefit of the whole research community. Results: We developed an automatic and comprehensive protein-DNA complex structure analysis program, PDA (for protein-DNA complex structure analyzer). PDA takes PDB files as inputs and performs structural analysis that includes 1) whole protein-DNA complex structure restoration, especially the reconstruction of double-stranded DNA structures;2) an efficient new approach for DNA base-pair detection;3) systematic annotation of protein-DNA interactions;and 4) extraction of DNA subsequences involved in protein-DNA interactions and identification of protein-DNA binding units. protein-DNA complex structures in current PDB were processed and analyzed with our PDA program and the analysis results were stored in a database. A dataset useful for studying protein-DNA interactions involved in gene regulation was generated using both protein and DNA sequences as well as the contact information of the complexes. WebPDA was developed to provide a web interface for using PDA and for data retrieval. Conclusion: PDA is a computational tool for structural annotations of protein-DNA complexes. It provides a useful resource for investigating protein-DNA interactions. data from the PDA analysis can also facilitat

关键词： protein data bank Matthews Correlation Coefficient protein data bank file protein data bank Entry Stagger Distance

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Deriving Function From Structure

Deriving Function From Structure

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作者： Annabel E. Todd

The fold and biochemical activity of a protein are tightly coupled. Once a protein is characterized, it is usual to determine its structure in order to derive an atomic descrip- tion of its molecular mechanism. The fo... 详细信息

关键词： protein data bank Functional Site protein data bank file Functional Residue Triacylglycerol Lipase

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