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Cunliang Geng, Anna Vangone, Gert E Folkers, Li C Xue, Alexandre M J J Bonvin
Quantitative evaluation of binding affinity changes upon mutations is crucial for protein engineering and drug design. Machine learning-based methods are gaining increasing momentum in this field. Due to the limited number of experimental data, using a small number of sensitive predictive features is vital to the generalization and robustness of such machine learning methods. Here we introduce a fast and reliable predictor of binding affinity changes upon single point mutation, based on a random forest approach...
November 12, 2018: Proteins
Abdulhameed Al-Ghabkari, Lori D Moffat, Michael P Walsh, Justin A MacDonald
Zipper-interacting protein kinase (ZIPK) is a Ser/Thr kinase that mediates a variety of cellular functions. Analogue-sensitive kinase technology was applied to the study of ZIPK signaling in coronary artery smooth muscle cells. ZIPK was engineered in the ATP-binding pocket by substitution of a bulky gatekeeper amino acid (Leu93) with glycine. Cell-permeable derivatives of pyrazolo[3,4-d]pyrimidine provided effective inhibition of L93G-ZIPK (1NM-PP1, IC50 , 1.0 μM; 3MB-PP1, IC50 , 2.0 μM; and 1NA-PP1, IC50 , 8...
November 1, 2018: Proteins
Mark A Hallen
Protein design algorithms must search an enormous conformational space to identify favorable conformations. As a result, those that perform this search with guarantees of accuracy generally start with a conformational pruning step, such as dead-end elimination (DEE). However, the mathematical assumptions of DEE-based pruning algorithms have up to now severely restricted the biophysical model that can feasibly be used in protein design. To lift these restrictions, I propose to prune local unrealistic geometries (PLUG) using a linear programming-based method...
October 31, 2018: Proteins
Tatjana Škrbić, Trinh X Hoang, Amos Maritan, Jayanth R Banavar, Achille Giacometti
A phase of matter is a familiar notion for inanimate physical matter. The nature of a phase of matter transcends the microscopic material properties. For example, materials in the liquid phase have certain common properties independent of the chemistry of the constituents: liquids take the shape of the container; they flow; and they can be poured - alcohol, oil and water as well as a Lennard-Jones computer model exhibit similar behavior when poised in the liquid phase. Here we identify a hitherto unstudied 'phase' of matter, the elixir phase, in a simple model of a polymeric chain whose backbone has the correct local cylindrical symmetry induced by the tangent to the chain...
October 29, 2018: Proteins
Erik Pfeiffenberger, Paul A Bates
Accurate protein-protein complex prediction, to atomic detail, is a challenging problem. For flexible docking cases, current state-of-the-art docking methods are limited in their ability to exhaustively search the high dimensionality of the problem space. In this study, to obtain more accurate models, an investigation into the local optimization of initial docked solutions is presented with respect to a reference crystal structure. We show how physics-based refinement of protein-protein complexes in contact map space (CMS), within a metadynamics protocol, can be performed...
October 29, 2018: Proteins
Chunjie Liang, Jiang Zhu, Theresa A Ramelot, Michael A Kennedy, Xiali Yue, Xuegang Li, Maili Liu, Ting He, Yunhuang Yang
We report the solution NMR structure of CHU_1110 from Cytophaga hutchinsonii. CHU_1110 contains three α-helices and one antiparallel β-sheet, forming a large cavity in the center of the protein, which are consistent with the structural characteristics of AHSA1 protein family. This protein shows high structural similarities to the prokaryotic proteins RHE_CH02687 from R. etli and YndB from B. subtilis, which can bind with flavinoids. Unlike these two homologs, CHU_1110 shows no obvious interaction with flavonoids in NMR titration experiments...
October 28, 2018: Proteins
Arpita Srivastava, Florence Tama, Daisuke Kohda, Osamu Miyashita
The translocase of the outer membrane (TOM) mediates the membrane permeation of mitochondrial matrix proteins. Tom20 is a subunit of the TOM complex and binds to the N-terminal region (i.e., presequence) in mitochondrial matrix precursor proteins. Previous experimental studies indicated that the presequence recognition by Tom20 was achieved in a dynamic-equilibrium among multiple bound states of the α-helical presequence. Accordingly, the co-crystallization of Tom20 and a presequence peptide required a disulfide-bond cross-linking...
October 27, 2018: Proteins
Omneya M Nassar, Changhong Li, Charles A Stanley, B Montgomery Pettitt, Thomas J Smith
Mammalian glutamate dehydrogenase (GDH) has complex allosteric regulation that is essential for a number of essential pathways (21). In particular, the loss of GTP inhibition causes the hyperinsulinism/hyperammonemia syndrome (HHS) where insulin is hypersecreted upon consumption of protein. The archetypical HHS lesion is H454Y and lies in the GTP binding pocket. To better understand the mechanism of HHS, we determined the crystal structure of this mutant. The mutation effects are limited to the H454Y GTP contacts...
October 27, 2018: Proteins
Manuel I Osorio, Matías A Zúñiga, Fernanda Mendoza, Gonzalo A Jaña, Verónica A Jiménez
Glucansucrase GTF-SI from Streptococcus mutans is an extracellular enzyme that catalyzes the synthesis of glucan polymers on teeth. GTF-SI has five domains: A, B, C, IV and V, with domain A containing the catalytic site, flanked by domains B and C. Domain V locates 100 Å away from the catalytic site and is required for an optimal enzymatic activity. Nevertheless, the crystal structure of GTF-SI containing domain V is not available, and the structural mechanism through which domain V participates in glucan synthesis still remains elusive...
October 27, 2018: Proteins
Roberto Paciotti, Loriano Storchi, Alessandro Marrone
The elucidation of the molecular mechanisms subtending the pathogenesis of prion diseases, and, the particular, of the events leading to the formation of prion particles is a nowadays challenge in the field of neurochemistry. A notable example is represented by pathogenic mutants of prion protein characterized by both an intrinsic tendency to aggregation and scrapie conversion propensity. However, the question about a possible correlation between these two events lasts still unanswered. Here, a multilayered computational workflow was employed to investigate structure, stability, and molecular interaction properties of a dimer of PrPC -E200K, a well-known mutant of the prion protein, that represents a reduced model of early aggregates of this protein...
October 27, 2018: Proteins
Casper Wilkens, Manish K Tiwari, Helen Webb, Murielle Jam, Mirjam Czjzek, Birte Svensson
In the marine environment agar degradation is assured by bacteria that contain large agarolytic systems with enzymes acting in various endo- and exo-modes. Agarase A (AgaA) is an endo-glycoside hydrolase of family 16 considered to initiate degradation of agarose. Agaro-oligosaccharide binding at a unique surface binding site (SBS) in AgaA from Zobellia galactanivorans was investigated by computational methods in conjunction with a structure/sequence guided approach of site-directed mutagenesis probed by surface plasmon resonance binding analysis of agaro-oligosaccharides of DP 4-10...
October 13, 2018: Proteins
Katie L Stewart, Deepali Rathore, Eric D Dodds, Matthew H J Cordes
The amino-acid sequences of soluble, globular proteins must have hydrophobic residues to form a stable core, but excess sequence hydrophobicity can lead to loss of native state conformational specificity and aggregation. Previous studies of polar-to-hydrophobic mutations in the β-sheet of the Arc repressor dimer showed that a single substitution at position 11 (N11L) leads to population of an alternate dimeric fold in which the β-sheet is replaced by helix. Two additional hydrophobic mutations at positions 9 and 13 (Q9V and R13V) lead to population of a differently folded octamer along with both dimeric folds...
October 12, 2018: Proteins
Niloofar Khairkhah, Ali Namvar, Kimia Kardani, Azam Bolhassani
Epitope mapping has emerged as a powerful tool to develop peptide vaccines against hypervariable viruses such as HIV. This method has led to stimulate a specific immune response and achieve advanced vaccine formulations. In this study, we identified peptides that were potentially immunostimulatory and highly conserved in HIV-1 main group. The analyses included were CTL assay, Tap transport, and the potential allergenicity. The highest population coverage rate was also found for all potential T-cell epitopes in 16 specified geographic regions of the world...
September 27, 2018: Proteins
Qianqian Wang, Ying Li, Jiahui Xu, Yuwei Wang, Danfeng Shi, Liang Liu, Elaine Lai-Han Leung, Xiaojun Yao
As a representative member of the bromodomain and extraterminal domain (BET) family, BRD4 is considered as a potential therapeutic target for cancer treatment. However, due to the highly conservation of its two homologous bromodomains (BD1/BD2), selective inhibition of each bromodomain remains a challenge. MS402 is a domain-selective inhibitor of BRD4-BD1 over BRD4-BD2 reported recently. Understanding the detailed molecular mechanism of this selectivity would be very useful for the further design and discovery of more potent selective inhibitors targeting BRD4-BD1...
September 27, 2018: Proteins
Jianzhong Chen, Cheng Peng, Jinan Wang, Weiliang Zhu
Recently, allosteric regulations of HIV-1 protease (PR) are suggested as a promising approach to relieve drug resistance of mutations toward inhibitors targeting the active site of PR. Replica-exchange molecular dynamics (REMD) simulations and normal mode analysis (NMA) are integrated to enhance conformational sampling of PR. Molecular mechanics generalized Born surface area (MM-GBSA) method was applied to calculate binding free energies of three inhibitors APV, DRV, and NIT to the wild-type (WT) and multidrug resistance (MDR) PRs...
September 27, 2018: Proteins
Swagata Pahari, Lexuan Sun, Sankar Basu, Emil Alexov
DelPhiPKa is a widely used and unique approach to compute pKa 's of ionizable groups that does not require molecular surface to be defined. Instead, it uses smooth Gaussian-based dielectric function to treat computational space via Poisson-Boltzmann equation (PBE). Here, we report an expansion of DelPhiPKa functionality to enable inclusion of salt in the modeling protocol. The method considers the salt mobile ions in solvent phase without defining solute-solvent boundary. Instead, the ions are penalized to enter solute interior via a desolvation penalty term in the Boltzmann factor in the framework of PBE...
September 25, 2018: Proteins
Vincenzo Carbone, Linley R Schofield, Carrie Sang, Andrew J Sutherland-Smith, Ron S Ronimus
The crystal structure of UDP-N-acetylglucosamine 4-epimerase (UDP-GlcNAc 4-epimerase; WbpP; EC, from the archaeal methanogen Methanobrevibacter ruminantium strain M1, was determined to a resolution of 1.65 Å. The structure, with a single monomer in the crystallographic asymmetric unit, contained a conserved N-terminal Rossmann-fold for nucleotide binding and an active site positioned in the C-terminus. UDP-GlcNAc 4-epimerase is a member of the short-chain dehydrogenases/reductases superfamily, sharing sequence motifs and structural elements characteristic of this family of oxidoreductases and bacterial 4-epimerases...
September 22, 2018: Proteins
Vinícius G Contessoto, Vinícius M de Oliveira, Bruno R Fernandes, Gabriel G Slade, Vitor B P Leite
The TKSAMC is a web server which calculates protein charge-charge interactions via the Tanford-Kirkwood Surface Accessibility model with the Monte Carlo method for sampling different protein protonation states. The optimization of charge-charge interactions via directed mutations has successfully enhanced the thermal stability of different proteins and could be a key to protein engineering improvement. The server presents the electrostatic free energy contribution of each polar-charged residue to the protein native state stability...
September 14, 2018: Proteins
B W J Irwin, Siniša Vukovič, M C Payne, Mohammad ElGamacy, P-L Chau
We have performed docking simulations on GABARAP interacting with the GABA type A receptor using SwarmDock. We have also used a novel method to study hydration sites on the surface of these two proteins; this method identifies regions around proteins where desolvation is relatively easy, and these are possible locations where proteins can bind each other. There is a high degree of consistency between the predictions of these two methods. Moreover, we have also identified binding sites on GABARAP for other proteins, and listed possible binding sites for as yet unknown proteins on both GABARAP and the GABA type A receptor intracellular domain...
September 14, 2018: Proteins
R N V Krishna Deepak, Ahmad Abdullah, Priti Talwar, Hao Fan, Palaniyandi Ravanan
The regulation of apoptosis is a tightly coordinated process and caspases are its chief regulators. Of special importance are the executioner caspases, caspase-3/7, the activation of which irreversibly sets the cell on the path of death. Dysregulation of apoptosis, particularly an increased rate of cell death lies at the root of numerous human diseases. Although several peptide-based inhibitors targeting the homologous active site region of caspases have been developed, owing to their non-specific activity and poor pharmacological properties their use has largely been restricted...
September 8, 2018: Proteins
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