| 1. |
- Deng, Min, et al.
(författare)
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Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis
- 2013
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 45:6, s. 697-
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Tidskriftsartikel (refereegranskat)abstract
- To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, P-combined = 2.92 x 10(-8), odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, P-combined = 2.35 x 10(-9), OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.
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| 2. |
- Deng, Tingzhi, et al.
(författare)
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Hippocampal Transcriptome-Wide Association Study Reveals Correlations Between Impaired Glutamatergic Synapse Pathway and Age-Related Hearing Loss in BXD-Recombinant Inbred Mice
- 2021
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Ingår i: Frontiers in Neuroscience. - : Frontiers Media S.A.. - 1662-4548 .- 1662-453X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Age-related hearing loss (ARHL) is associated with cognitive dysfunction; however, the detailed underlying mechanisms remain unclear. The aim of this study is to investigate the potential underlying mechanism with a system genetics approach. A transcriptome-wide association study was performed on aged (12-32 months old) BXD mice strains. The hippocampus gene expression was obtained from 56 BXD strains, and the hearing acuity was assessed from 54 BXD strains. Further correlation analysis identified a total of 1,435 hearing-related genes in the hippocampus (p < 0.05). Pathway analysis of these genes indicated that the impaired glutamatergic synapse pathway is involved in ARHL (p = 0.0038). Further gene co-expression analysis showed that the expression level of glutamine synthetase (Gls), which is significantly correlated with ARHL (n = 26, r = -0.46, p = 0.0193), is a crucial regulator in glutamatergic synapse pathway and associated with learning and memory behavior. In this study, we present the first systematic evaluation of hippocampus gene expression pattern associated with ARHL, learning, and memory behavior. Our results provide novel potential molecular mechanisms involved in ARHL and cognitive dysfunction association.
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| 3. |
- Yin, Chunhua, et al.
(författare)
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Role of Host-Guest Charge Transfer in Cyclodextrin Complexation : A Computational Study
- 2019
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Ingår i: The Journal of Physical Chemistry C. - : AMER CHEMICAL SOC. - 1932-7447 .- 1932-7455. ; 123:29, s. 17745-17756
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Tidskriftsartikel (refereegranskat)abstract
- Charge transfer (CT) was proposed to play a role in the cyclodextrin (CD) complexation with guest molecules. To elucidate the importance of CT interactions, here we used computational methods of quantum mechanics, docking, and molecular dynamics (MD) to investigate alpha-CD complexes with aromatic guest molecules of nitrobenzene, carboxybenzene, benzoate, 4-nitrophenol, and 4-nitrophenolate. Considering host guest CT in the docking has more of a chance to search reasonable guest orientations relative to alpha-CD matching the experiment, compared to that without CT. The CT interaction enlarges the difference in binding affinities of varied guests, as evidenced from potential of mean force (PMF) MD calculations. Energy decomposition of the total enthalpy and entropy shows the CT influence on the binding reactions in detail and indicates that there are considerable compensating effects of individual contributions from the binding partners and surrounding water. Charge transfer reduces the total dipole of alpha-CD by 9% on average and alters its dipole direction thereby affecting guest association. Gas-phase zeroth-order symmetry-adapted perturbation theory calculations show host guest CT amounts to approximately 6% of the total binding energy. The continuum solvation model based on the quantum mechanical charge density predicts binding energies comparable with the well depth of PMF profiles in explicit water. The abnormal binding strength of alpha-CD with the similar guests can be rationalized in terms of hydrogen bonding, extent of host guest CT, and dipole arrangement of guest relative to host.
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| 4. |
- Zhang, Haiyang, et al.
(författare)
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Evaluation of Generalized Born Models for Large Scale Affinity Prediction of Cyclodextrin Host-Guest Complexes
- 2016
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 56:10, s. 2080-2092
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Tidskriftsartikel (refereegranskat)abstract
- Binding affinity prediction with implicit solvent models remains a challenge in virtual screening for drug discovery. In order to assess the predictive power of implicit solvent models in docking techniques with Amber scoring, three generalized Born models (GB(HCT), GB(OBC)I, and GB(OBC)II) available in Dock 6.7 were utilized, for determining the binding affinity of a large set of beta-cydodextrin complexes with 75 neutral guest molecules. The results were compared to potential of mean force (PMF) free energy calculations with four GB models (GB(Still), GB(HCT), GB(OBC)I, and GB(OBC)II and to experimental data. Docking results yield similar accuracy to the computationally demanding PMF method with umbrella sampling. Neither docking nor PMF calculations reproduce the experimental binding affinities, however, as indicated by a small Spearman rank order coefficient (similar to 0.5). The binding energies obtained from GB models were decomposed further into individual contributions of the binding partners and solvent environments and compared to explicit solvent simulations for five complexes allowing for rationalizing the difference between explicit and implicit solvent models. An important observation is that the explicit solvent screens the interaction between host and guest much stronger than GB models. In contrast, the screening in GB models is too strong in solutes, leading to overestimation of short-range interactions and too strong binding. It is difficult to envision a way of overcoming these two opposite effects.
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| 5. |
- Zhang, Haiyang, et al.
(författare)
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Force Field Benchmark of Amino Acids : I. Hydration and Diffusion in Different Water Models
- 2018
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Ingår i: Journal of Chemical Information and Modeling. - : American Chemical Society (ACS). - 1549-9596 .- 1549-960X. ; 58:5, s. 1037-1052
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Tidskriftsartikel (refereegranskat)abstract
- Thermodynamic and kinetic properties are of critical importance for the applicability of computational models to biomolecules such as proteins. Here we present an extensive evaluation of the Amber ff99SB-ILDN force field for modeling of hydration and diffusion of amino acids with three-site (SPC, SPC/E, SPC/E-b , and TIP3P), four-site (TIP4P, TIP4P-Ew, and TIP4P/2005), and five-site (TIPSP and TIP5P-Ew) water models. Hydration free energies (HFEs) of neutral amino acid side chain analogues have little dependence on the water model, with a root-mean-square error (RMSE) of similar to 1 kcal/mol from experimental observations. On the basis of the number of interacting sites in the water model, HFEs of charged side chains can be putatively classified into three groups, of which the group of three-site models lies between those of four- and five-site water models; for each group, the water model dependence is greatly eliminated when the solvent Galvani potential is considered. Some discrepancies in the location of the first hydration peak (R-RDF) in the ion-water radial distribution function between experimental and calculated observations were detected, such as a systematic underestimation of the acetate (Asp side chain) ion. The RMSE of calculated diffusion coefficients of amino acids from experiment increases linearly with the increasing diffusion coefficients of the solvent water models at infinite dilution. TIP3P has the fastest diffusivity, in line with literature findings, while the "FB" and "OPC" water model families as well as TIP4P/2005 perform well, within a relative error of 5%, and TIP4P/2005 yields the most accurate estimate for the water diffusion coefficient. All of the tested water models overestimate amino acid diffusion coefficients by approximately 40% (TIP4P/2005) to 200% (TIP3P). Scaling of protein-water interactions with TIP4P/2005 in the Amber ff99SBws and ff03ws force fields leads to more negative HFEs but has little influence on the diffusion of amino acids. The most recent FF/water combinations of ff14SB/OPC3, ffl5ipq/SPC/E-b, and fb15/TIP3P-FB do not show obvious improvements in accuracy for the tested quantities. These findings here establish a benchmark that may aid in the development and improvement of classical force fields to accurately model protein dynamics and thermodynamics.
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| 6. |
- Zhang, Haiyang, et al.
(författare)
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Free-Energy Calculations of Ionic Hydration Consistent with the Experimental Hydration Free Energy of the Proton
- 2017
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Ingår i: The Journal of Physical Chemistry Letters. - : AMER CHEMICAL SOC. - 1948-7185. ; 8:12, s. 2705-2712
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Tidskriftsartikel (refereegranskat)abstract
- Computational free-energy correction strategies and the choice of experimental proton hydration free energy, Delta G(s)*(H+), are analyzed to investigate the apparent controversy in experimental thermodynamics of ionic hydration. Without corrections, the hydration free-energy (Delta G(hyd)) calculations match experiments with Delta G(s)*(H+) = -1064 kJ/mol as reference. Using the Galvani surface potential the resulting (real) Delta G(s)* are consistent with Delta G(s)*(H+) = -1098 kJ/mol. When applying, in an ad hoc manner, the discrete solvent correction, G(hyd) matching the "consensus" Delta G(s)*(H+) of -1112 kJ/mol are obtained. This analysis rationalizes reports on Delta G(hyd) calculations for ions using different experimental references. For neutral amino acid side chains Delta G(hyd) are independent of the water model, whereas there are large differences in Delta G(hyd) due to the water model for charged species, suggesting that long-range ordering of water around ions yields an important contribution to the Delta G(hyd). These differences are reduced significantly when applying consistent corrections, but to obtain the most accurate results it is recommended to use the water model belonging to the force field.
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