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1.
ImmunomeBrowser: a tool to aggregate and visualize complex and heterogeneous epitopes in reference proteins.
Dhanda, SK, Vita, R, Ha, B, Grifoni, A, Peters, B, Sette, A
Bioinformatics (Oxford, England). 2018;(22):3931-3933
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Abstract
MOTIVATION Datasets that are derived from different studies (e.g. MHC ligand elution, MHC binding, B/T cell epitope screening etc.) often vary in terms of experimental approaches, sizes of peptides tested, including partial and or nested overlapping peptides and in the number of donors tested. RESULTS We present a customized application of the Immune Epitope Database's ImmunomeBrowser tool, which can be used to effectively aggregate and visualize heterogeneous immunological data. User provided peptide sets and associated response data is mapped to a user-provided protein reference sequence. The output consists of tables and figures representing the aggregated data represented by a Response Frequency score and associated estimated confidence interval. This allows the user to visualizing regions associated with dominant responses and their boundaries. The results are presented both as a user interactive javascript based web interface and a tabular format in a selected reference sequence. AVAILABILITY AND IMPLEMENTATION The 'ImmunomeBrowser' has been a longstanding feature of the IEDB (http://www.iedb.org). The present application extends the use of this tool to work with user-provided datasets, rather than the output of IEDB queries. This new server version of the ImmunomeBrowser is freely accessible at http://tools.iedb.org/immunomebrowser/.
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Narrowing the gap between experimental and computational determination of methyl group dynamics in proteins.
Hoffmann, F, Xue, M, Schäfer, LV, Mulder, FAA
Physical chemistry chemical physics : PCCP. 2018;(38):24577-24590
Abstract
Nuclear magnetic resonance (NMR) spin relaxation has become the mainstay technique to sample protein dynamics at atomic resolution, expanding its repertoire from backbone 15N to side-chain 2H probes. At the same time, molecular dynamics (MD) simulations have become increasingly powerful to study protein dynamics due to steady improvements of physical models, algorithms, and computational power. Good agreement between generalized Lipari-Szabo order parameters derived from experiment and MD simulation has been observed for the backbone dynamics of a number of proteins. However, the agreement for the more dynamic side-chains, as probed by methyl group relaxation, was much worse. Here, we use T4 lysozyme (T4L), a protein with moderate tumbling anisotropy, to showcase a number of improvements that reduce this gap by a combined evaluation of NMR relaxation experiments and MD simulations. By applying a protein force field with accurate methyl group rotation barriers in combination with a solvation model that yields correct protein rotational diffusion times, we find that properly accounting for anisotropic protein tumbling is an important factor to improve the match between NMR and MD in terms of methyl axis order parameters, spectral densities, and relaxation rates. The best agreement with the experimentally measured relaxation rates is obtained by a posteriori fitting the appropriate internal time correlation functions, truncated by anisotropic overall tumbling. In addition, MD simulations led us to account for a hitherto unrealized artifact in deuterium relaxation experiments arising from strong coupling for leucine residues in uniformly 13C-enriched proteins. For T4L, the improved analysis reduced the RMSD between MD and NMR derived methyl axis order parameters from 0.19 to 0.11. At the level of the spectral density functions, the improvements allow us to extract the most accurate parameters that describe protein side-chain dynamics. Further improvement is challenging not only due to force field and sampling limitations in MD, but also due to inherent limitations of the Lipari-Szabo model to capture complex dynamics.
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Effective lead optimization targeting the displacement of bridging receptor-ligand water molecules.
Chen, D, Li, Y, Zhao, M, Tan, W, Li, X, Savidge, T, Guo, W, Fan, X
Physical chemistry chemical physics : PCCP. 2018;(37):24399-24407
Abstract
Enhancing the binding affinities of ligands by means of lead modifications that displace bridging water molecules at protein-ligand interfaces is an important and widely studied lead optimization strategy. However, it is still challenging to ensure the success of this lead optimization strategy. Here we use theoretical derivations, which are then validated using reported experimental data, to identify the major determining factors in lead optimization designed to displace bridging water molecules. Our findings demonstrate that the nature of hydrogen-bond pairing between the ligand and protein polar atom(s) is the principal factor displacing interface water molecules, and not the binding strength of the water molecule. Our results also indicate that all interfacing bridging water molecules can potentially be targeted for displacement using this new approach. In summary, we show that strong-strong/weak-weak hydrogen-bond pairings of ligand atoms with protein atoms may provide useful guidance in lead modifications by designing modified ligands with higher binding affinities than their lead molecules. This study can help to increase the efficiency of rational drug design.
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Metabolomics Reveals that the Type of Protein in a High-Fat Meal Modulates Postprandial Mitochondrial Overload and Incomplete Substrate Oxidation in Healthy Overweight Men.
Pujos-Guillot, E, Brandolini-Bunlon, M, Fouillet, H, Joly, C, Martin, JF, Huneau, JF, Dardevet, D, Mariotti, F
The Journal of nutrition. 2018;(6):876-884
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Abstract
BACKGROUND A meal rich in saturated fatty acids induces a postprandial metabolic challenge. The type of dietary protein may modulate postprandial metabolism. OBJECTIVE We studied the effect of dietary protein type on postprandial changes in the metabolome after a high-fat meal. METHODS In a 3-period, crossover, postprandial study, 10 healthy overweight men with an elevated waist circumference (>94 cm) ingested high-fat meals made up of cream fat (70% of energy), sucrose (15% energy), and protein (15% energy) from either casein (CAS), whey protein (WHE), or α-lactalbumin-enriched whey protein (LAC). Urine collected immediately before and 2, 4, and 6 h after the meal was analyzed for metabolomics, a secondary outcome of the clinical study. We used mixed-effect models, partial least-square regression, and pathway enrichment analysis. RESULTS At 4 and 6 h after the meal, the postprandial metabolome was found to be fully discriminated according to protein type. We identified 17 metabolites that significantly explained the effect of protein type on postprandial metabolomic changes (protein-time interaction). Among this signature, acylcarnitines and other acylated metabolites related to fatty acid or amino acid oxidation were the main discriminant features. The difference in metabolic profiles was mainly explained by urinary acylcarnitines and some other acylated products (protein type, Ps < 0.0001), with a dramatically greater increase (100- to 1000-fold) after WHE, and to a lesser extent after LAC, as compared with CAS. Pathway enrichment analysis confirmed that the type of protein had modified fatty acid oxidation (P < 0.05). CONCLUSION Taken together, our results indicate that, in healthy overweight men, the type of protein in a high-fat meal interplays with fatty acid oxidation with a differential accumulation of incomplete oxidation products. A high-fat meal containing WHE, but not CAS, resulted in this outpacing of the tricarboxylic acid cycle. This study was registered at clinicaltrials.gov as NCT00931151.
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The effects of angiotensin receptor neprilysin inhibition by sacubitril/valsartan on adipose tissue transcriptome and protein expression in obese hypertensive patients.
Stinkens, R, van der Kolk, BW, Jordan, J, Jax, T, Engeli, S, Heise, T, Jocken, JW, May, M, Schindler, C, Havekes, B, et al
Scientific reports. 2018;(1):3933
Abstract
Increased activation of the renin-angiotensin system is involved in the onset and progression of cardiometabolic diseases, while natriuretic peptides (NP) may exert protective effects. We have recently demonstrated that sacubitril/valsartan (LCZ696), a first-in-class angiotensin receptor neprilysin inhibitor, which blocks the angiotensin II type-1 receptor and augments natriuretic peptide levels, improved peripheral insulin sensitivity in obese hypertensive patients. Here, we investigated the effects of sacubitril/valsartan (400 mg QD) treatment for 8 weeks on the abdominal subcutaneous adipose tissue (AT) phenotype compared to the metabolically neutral comparator amlodipine (10 mg QD) in 70 obese hypertensive patients. Abdominal subcutaneous AT biopsies were collected before and after intervention to determine the AT transcriptome and expression of proteins involved in lipolysis, NP signaling and mitochondrial oxidative metabolism. Both sacubitril/valsartan and amlodipine treatment did not significantly induce AT transcriptional changes in pathways related to lipolysis, NP signaling and oxidative metabolism. Furthermore, protein expression of adipose triglyceride lipase (ATGL) (Ptime*group = 0.195), hormone-sensitive lipase (HSL) (Ptime*group = 0.458), HSL-ser660 phosphorylation (Ptime*group = 0.340), NP receptor-A (NPRA) (Ptime*group = 0.829) and OXPHOS complexes (Ptime*group = 0.964) remained unchanged. In conclusion, sacubitril/valsartan treatment for 8 weeks did not alter the abdominal subcutaneous AT transcriptome and expression of proteins involved in lipolysis, NP signaling and oxidative metabolism in obese hypertensive patients.
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ComplexContact: a web server for inter-protein contact prediction using deep learning.
Zeng, H, Wang, S, Zhou, T, Zhao, F, Li, X, Wu, Q, Xu, J
Nucleic acids research. 2018;(W1):W432-W437
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Abstract
ComplexContact (http://raptorx2.uchicago.edu/ComplexContact/) is a web server for sequence-based interfacial residue-residue contact prediction of a putative protein complex. Interfacial residue-residue contacts are critical for understanding how proteins form complex and interact at residue level. When receiving a pair of protein sequences, ComplexContact first searches for their sequence homologs and builds two paired multiple sequence alignments (MSA), then it applies co-evolution analysis and a CASP-winning deep learning (DL) method to predict interfacial contacts from paired MSAs and visualizes the prediction as an image. The DL method was originally developed for intra-protein contact prediction and performed the best in CASP12. Our large-scale experimental test further shows that ComplexContact greatly outperforms pure co-evolution methods for inter-protein contact prediction, regardless of the species.
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A Deep Phenotype Association Study Reveals Specific Phenotype Associations with Genetic Variants in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 (AREDS2) Report No. 14.
van Asten, F, Simmons, M, Singhal, A, Keenan, TD, Ratnapriya, R, Agrón, E, Clemons, TE, Swaroop, A, Lu, Z, Chew, EY, et al
Ophthalmology. 2018;(4):559-568
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Abstract
PURPOSE Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. DESIGN Cohort study. PARTICIPANTS AREDS and AREDS2 participants. METHODS AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. MAIN OUTCOME MEASURES Genotype-phenotype associations. RESULTS A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31-1.84], P = 2.67 × 10-7). This novel association remained significant after conditioning on participants with neovascular AMD (P = 2.42 × 10-4). Carriers of rs3750846 had poorer visual acuity during follow-up (P = 6.82 × 10-7) and were more likely to have a first-degree relative with AMD (P = 5.38 × 10-6). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment Diabetic Retinopathy Study Report (ETDRS) grid (P = 2.29 × 10-11 and P = 3.20 × 10-9, respectively) and the center subfield (P = 1.24 × 10-9 and P = 6.68 × 10-8, respectively). SNP rs570618 was additionally associated with the presence of calcified drusen (P = 5.38 × 10-6). Except for positive family history of AMD with rs3750846, all genotype-phenotype associations were significantly replicated in AREDS. No pleiotropic associations were identified. CONCLUSIONS The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poorer visual acuity and of SNPs at the CFH locus with drusen area may provide new insights in pathophysiological pathways underlying different stages of AMD.
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R106C TFG variant causes infantile neuroaxonal dystrophy "plus" syndrome.
Catania, A, Battini, R, Pippucci, T, Pasquariello, R, Chiapparini, ML, Seri, M, Garavaglia, B, Zorzi, G, Nardocci, N, Ghezzi, D, et al
Neurogenetics. 2018;(3):179-187
Abstract
TFG (tropomyosin-receptor kinase fused gene) encodes an essential protein in the regulation of vesicular trafficking between endoplasmic reticulum and Golgi apparatus. The homozygous variant c.316C > T within TFG has been previously associated with a complicated hereditary spastic paraplegia (HSP) phenotype in two unrelated Indian families. Here, we describe the first Italian family with two affected siblings harboring the same variant, who in childhood were classified as infantile neuroaxonal dystrophy (INAD) based on clinical and neuropathological findings. Twenty years after the first diagnosis, exome sequencing was instrumental to identify the genetic cause of this disorder and clinical follow-up of patients allowed us to reconstruct the natural history of this clinical entity. Investigations on patient's fibroblasts demonstrate the presence of altered mitochondrial network and inner membrane potential, associated with metabolic impairment. Our study highlights phenotypic heterogeneity characterizing individuals carrying the same pathogenic variant in TFG and provides an insight on tight connection linking mitochondrial efficiency and neuronal health to vesicular trafficking.
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The role of renal response to amino acid infusion and oral protein load in normal kidneys and kidney with acute and chronic disease.
Gabbai, FB
Current opinion in nephrology and hypertension. 2018;(1):23-29
Abstract
PURPOSE OF REVIEW High protein intake and hyperfiltration have been a focus of major interest as potential mechanism(s) of progression of renal disease. This review will examine: the renal response to a protein meal or amino acid infusion and its use to test the renal functional reserve (RFR); new methods to evaluate RFR; the use of RFR in various pathophysiologic conditions. RECENT FINDINGS The renal response to protein/amino acid infusion involves several mechanisms, including nitric oxide, insulin, glucagon, arginine vasopressin, urea, the renal N-Methyl-D-Aspartate Glutamate receptor and modulation of the activity of the tubuloglomerular feedback system. Dose-response studies to evaluate RFR suggest the presence of a potential ceiling. The utilization of a noninvasive technique such as Doppler ultrasonography is trying to simplify the measurement of RFR and to bring this test into different clinical settings. There is increased interest in the presence or absence of RFR in patients with acute kidney injury, hypertension, chronic kidney disease, and its potential long-term implication regarding renal function. SUMMARY The renal response to protein may help us understand the relationship between hyperfiltration, progression of renal disease, and other conditions (overall mortality, cardiovascular complications, and so on) currently being explored.
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Self-assembled mechanism of hydrophobic amino acids and β-cyclodextrin based on experimental and computational methods.
Li, J, Geng, S, Liu, B, Wang, H, Liang, G
Food research international (Ottawa, Ont.). 2018;:136-142
Abstract
The β-cyclodextrin (β-CD) can be used to remove bitter taste of protein hydrolysates, which is attributed to its interaction with hydrophobic amino acids included within peptides. But the corresponding mechanism has not been fully clarified. Herein, we systematically investigate the interaction between β-CD and three hydrophobic amino acids involving tryptophan (Trp), tyrosine (Tyr), and phenylalanine (Phe). We prove the formation of amino acid/β-CD supermolecular complexes determined by FS, UV, IR, DSC and NMR, manifesting that no new chemical bond is formed in these complexes. The theoretical interaction conformations are given by molecule docking and further supported by ONIOM (our Own N-layer Integrated Orbital molecular Mechanics) calculations, with the consideration of structural assignments, binding orientations, solvent effects, interaction energies and main forces to form these complexes. Molecular docking results suggest that the hydrophobic amino acids prefer to interact with β-CD by their aromatic ring, meaning hydrophobic interactions are main forces for them entering into the cavity of β-CD. ONIOM-based calculations provide a number of quantum-chemical parameters to confirm our experimental results; meanwhile, to demonstrate that H-bonds play an important role in maintaining the stability of three amino acid/β-CD complexes. This work is help for demonstrating the interaction mechanism of amino acid/β-CD supermolecular system, and guiding how to remove bitterness or undesirable taste of bioactive peptides, even other interested molecules.