A Comparative Molecular Dynamics Study of Methylation State Specificity of JMJD2A

Histone modifications have great importance in epigenetic regulation. JMJD2A is a histone demethylase which is selective for di- and trimethyl forms of residues Lys9 and Lys36 of Histone 3 tail (H3K9 and H3K36). We present a molecular dynamics simulations of mono-, di- and trimethylated histone tails in complex with JMJD2A catalytic domain to gain insight into how JMJD2A discriminates between the methylation states of H3K9. The methyl groups are located at specific distances and orientations with respect to Fe(II) in methylammonium binding pocket. For the trimethyllysine the mechanism which provides the effectual orientation of methyl groups is the symmetry, whereas for the dimethyllysine case the determining factors are the interactions between methyllysine head and its environment and subsequently the restriction on angular motion. The occurrence frequency of methyl groups in a certain proximity of Fe(II) comes out as the explanation of the enzyme activity difference on di- and tri-methylated peptides. Energy analysis suggests that recognition is mostly driven by van der Waals and followed by Coulombic interactions in the enzyme-substrate interface. The number (mono, di or tri) and orientations of methyl groups and water molecules significantly affect the extent of van der Waals interaction strengths. Hydrogen bonding analysis suggests that the interaction between JMJD2A and its substrates mainly comes from main chain-side chain interactions. Binding free energy analysis points out Arg8 as an important residue forming an intra-substrate hydrogen bond with tri and dimethylated Lys9 of the H3 chain. Our study provides new insights into how JMJD2A discriminates between its substrates from both a structural and dynamical point of view

Energetics of Hydrophilic Protein–Protein Association and the Role of Water

Hydrophilic protein–protein interfaces constitute a major part of all protein–protein interfaces and are thus of great importance. However, the quantitative characterization of their association is still an ongoing challenge and the driving force behind their association remains poorly characterized. Here, we have addressed the association of hydrophilic proteins and the role of water by means of extensive molecular dynamics simulations in explicit water using three well studied protein complexes; Barnase–Barstar, cytochrome c–cytochrome c peroxidase, and the N-terminal domain of enzyme I-histidine-containing phosphocarrier. The one-dimensional free energy profiles obtained from umbrella sampling simulations are downhill or, in other words, barrierless. Using these one-dimensional free energy profiles, the computed standard free energies of binding are −12.7 ± 1.1 kcal/mol, −9.4 ± 0.7 kcal/mol, and −8.4 ± 1.9 kcal/mol that are in reasonable to very good agreement with the experimental values of −19.6 kcal/mol, −8.8 kcal/mol, and −7.8 kcal/mol. As expected, analysis of the confined water between the hydrophilic complex partners shows that the density and the orientational order parameter deviate noticeably from the bulk values, especially at close separations of the confining proteins

Nano-vesicular formulation of propolis and cytotoxic effects in a 3D spheroid model of lung cancer

Ulucan, Fulden/0000-0001-5567-0261; Yesil-Celiktas, Ozlem/0000-0003-4509-2212; saglam metiner, pelin/0000-0002-5726-1928WOS: 000526841800001PubMed: 32239766BACKGROUND Propolis exhibits therapeutic properties due to the presence of phenolic acids, esters, and flavonoids. the scope of this study was to develop a nano-vesicular formulation and establish a three-dimensional (3D) spheroid model in which lung cancer is recapitulated. RESULTS Niosome vesicles doped with galangin-rich propolis extract were synthesized by the ether injection method using a cholesterol : surfactant mass ratio of 1 : 3 at 40 degrees C for 1 h. Formulated niosomes were administered to 3D lung cancer spheroid model and the cytotoxicity was compared with that of a two-dimensional (2D) setting. the galangin content was determined as 86 mu g mg(-1) propolis extract by ultra-performance liquid chromatography (UPLC). the particle size of loaded niosome was 151 +/- 2.84 nm with a polydispersity index (PDI) of about 0.232, and an encapsulation efficiency of 70% was achieved. CONCLUSION the decrease in cell viability and the scattering in the 3D spheroids of A549 lung cancer cells treated with propolis-loaded niosomes were notable, indicating a profound cytotoxic effect and suggesting that they can be utilized as an effective nano-vesicle. (c) 2020 Society of Chemical Industr

Neuroprotective Effects of Lacosamide in Experimental Traumatic Spinal Cord Injury in Rats

AIM: To evaluate the effects of lacosamide on traumatic spinal cord injury (SCI) in rats

Genes That Affect Brain Structure And Function Identified By Rare Variant Analyses Of Mendelian Neurologic Disease

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations.WoSScopu

Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease

Development of the human nervous system involves complex interactions among fundamental cellular processes and requires a multitude of genes, many of which remain to be associated with human disease. We applied whole exome sequencing to 128 mostly consanguineous families with neurogenetic disorders that often included brain malformations. Rare variant analyses for both single nucleotide variant (SNV) and copy number variant (CNV) alleles allowed for identification of 45 novel variants in 43 known disease genes, 41 candidate genes, and CNVs in 10 families, with an overall potential molecular cause identified in >85% of families studied. Among the candidate genes identified, we found PRUNE, VARS, and DHX37 in multiple families and homozygous loss-of-function variants in AGBL2, SLC18A2, SMARCA1, UBQLN1, and CPLX1. Neuroimaging and in silico analysis of functional and expression proximity between candidate and known disease genes allowed for further understanding of genetic networks underlying specific types of brain malformations. VIDEO ABSTRACT.publisher: Elsevier articletitle: Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease journaltitle: Neuron articlelink: http://dx.doi.org/10.1016/j.neuron.2015.09.048 content_type: article copyright: Copyright © 2015 Elsevier Inc. All rights reserved.status: publishe