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https://www.readbyqxmd.com/read/28650719/computational-investigation-on-the-effects-of-h50q-and-g51d-mutations-on-the-%C3%AE-synuclein-aggregation-propensity
#1
Airy Sanjeev, Venkata Satish Kumar Mattaparthi
The aggregation of α-synuclein is linked directly to the histopathology of Parkinson's disease (PD). However, several missense mutations present in the α-synuclein gene (SNCA) have been known to be associated with PD. Several studies have highlighted the effect of SNCA mutations on the α-synuclein aggregation, but their pathological roles are not completely established. In this study, we have focused on the effects of the recently discovered α-synuclein missense mutants (H50Q and G51D) on the aggregation using computational approaches...
June 26, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28648081/in-silico-and-in-vitro-screening-for-p-glycoprotein-interaction-with-tenofovir-darunavir-and-dapivirine-an-anti-retroviral-drug-combination-for-topical-prevention-of-colorectal-hiv-transmission
#2
Magda Swedrowska, Shirin Jamshidi, Abhinav Kumar, Charles Kelly, K Miraz Rahman, Ben Forbes
The aim of the study was to use in-silico and in vitro techniques to evaluate whether a triple formulation of antiretroviral drugs (tenofovir, darunavir and dapivirine) interacted with p-glycoprotein (P-gp) or exhibited any other permeability-altering drug-drug interactions in the colorectal mucosa. Potential drug interactions with P-gp were screened initially using molecular docking, followed by molecular dynamics simulations to analyse the identified drug-transporter interaction more mechanistically. The transport of tenofovir, darunavir and dapivirine was investigated in the Caco-2 cells models and colorectal tissue and their apparent permeability coefficient (Papp), efflux ratio (ER) and the effect of transporter inhibitors were evaluated...
June 25, 2017: Molecular Pharmaceutics
https://www.readbyqxmd.com/read/28648071/elucidation-of-the-catalytic-mechanism-of-a-miniature-zinc-finger-hydrolase
#3
Abir Ganguly, Trung Quan Luong, Oliver Brylski, Michael Dirkmann, David Möller, Simon Ebbinghaus, Frank Schulz, Roland Winter, Elsa Sanchez-Garcia, Walter Thiel
To improve our mechanistic understanding of zinc metalloenzymes, we report a joint computational and experimental study of a minimal carbonic anhydrase (CA) mimic, a 22-residue Zn-finger hydrolase. We combine classical molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM) geometry optimizations, and QM/MM free energy simulations with ambient and high-pressure kinetic measurements to investigate the mechanism of the hydrolysis of the substrate p-nitrophenylacetate (pNPA). The zinc center of the hydrolase prefers a pentacoordinated geometry, as found in most naturally occurring CAs and CA-like enzymes...
June 24, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28645089/drug-resistance-mechanism-of-l10f-l10f-n88s-and-l90m-mutations-in-crf01_ae-hiv-1-protease-molecular-dynamics-simulations-and-binding-free-energy-calculations
#4
C S Vasavi, Ramasamy Tamizhselvi, Punnagai Munusami
HIV-1 protease plays a crucial role in viral replication and maturation, which makes it one of the most attractive targets for anti-retroviral therapy. The majority of HIV infections in developing countries are due to non-B subtype. Subtype AE is spreading rapidly and infecting huge population worldwide. The mutations in the active site of subtype AE directly impair the interactions with the inhibitor. The non-active site mutations influence the binding of the inhibitor indirectly and their resistance mechanism is not well understood...
June 8, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28644624/extensive-assessment-of-various-computational-methods-for-aspartate-s-pka-shift
#5
Zhaoxi Sun, Xiaohui Wang, Jianing Song
A series of computational methods for pKa shift prediction are extensively tested on a set of benchmark protein systems, aiming at identifying pitfalls and evaluating their performance on high variants. Including 19 ASP residues in 10 protein systems, the benchmark set consists of both residues with highly shifted pKa values as well as those varying little from the reference value, with an experimental RMS free energy differences of 2.49 kcal/mol with respect to blocked amino acid, namely the RMS pKa shift being 1...
June 23, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28641562/structural-characterization-of-amyloid-%C3%AE-17-42-dimer-by-potential-of-mean-force-analysis-insights-from-molecular-dynamics-simulations
#6
Mary Dutta, Rajkalyan Chutia, Venkata Satish Kumar Mattaparthi
Recent experiments with Amyloid β1-42 peptide have indicated that the initial dimerization of Aβ1-42 monomers to form amyloid dimers stand out as a key event in the generation of toxic oligomers. However, the structural characterization of Aβ1-42 dimer at the atomistic level and the dimerization mechanism by which Aβ1-42 peptides co-aggregate still remains not clear. In the present study, the process of Aβ17-42 peptide dimerization which is known to play an important role in the plaque formation was evaluated in terms of potential of mean force, which provided free energies along the reaction coordinates...
June 20, 2017: Protein and Peptide Letters
https://www.readbyqxmd.com/read/28641432/local-structure-of-dilute-aqueous-dmso-solutions-as-seen-from-molecular-dynamics-simulations
#7
Abdenacer Idrissi, Bogdan A Marekha, Mohammed Barj, François Alexandre Miannay, Toshiyuki Takamuku, Vasilios Raptis, Jannis Samios, Pál Jedlovszky
The information about the structure of dimethyl sulfoxide (DMSO)-water mixtures at relatively low DMSO mole fractions is an important step in order to understand their cryoprotective properties as well as the solvation process of proteins and amino acids. Classical MD simulations, using the potential model combination that best reproduces the free energy of mixing of these compounds, are used to analyze the local structure of DMSO-water mixtures at DMSO mole fractions below 0.2. Significant changes in the local structure of DMSO are observed around the DMSO mole fraction of 0...
June 21, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28641428/liquid-liquid-phase-transition-in-an-ionic-model-of-silica
#8
Renjie Chen, Erik Lascaris, Jeremy C Palmer
Recent equation of state calculations [E. Lascaris, Phys. Rev. Lett. 116, 125701 (2016)] for an ionic model of silica suggest that it undergoes a density-driven, liquid-liquid phase transition (LLPT) similar to the controversial transition hypothesized to exist in deeply supercooled water. Here, we perform extensive free energy calculations to scrutinize the model's low-temperature phase behavior and confirm the existence of a first-order phase transition between two liquids with identical compositions but different densities...
June 21, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28636916/structural-behavior-of-the-peptaibol-harzianin-hk-vi-in-a-dmpc-bilayer-insights-from-md-simulations
#9
Marina Putzu, Sezgin Kara, Sergii Afonin, Stephan L Grage, Andrea Bordessa, Grégory Chaume, Thierry Brigaud, Anne S Ulrich, Tomáš Kubař
Microsecond molecular dynamics simulations of harzianin HK VI (HZ) interacting with a dimyristoylphosphatidylcholine bilayer were performed at the condition of low peptide-to-lipid ratio. Two orientations of HZ molecule in the bilayer were found and characterized. In the orientation perpendicular to the bilayer surface, HZ induces a local thinning of the bilayer. When inserted into the bilayer parallel to its surface, HZ is located nearly completely within the hydrophobic region of the bilayer. A combination of solid-state NMR and circular dichroism experiments found the latter orientation to be dominant...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28636909/electric-field-induced-protein-translocation-via-a-conformational-transition-in-secdf-an-md-study
#10
Emel Ficici, Daun Jeong, Ioan Andricioaei
SecDF is an important component of the Sec protein translocation machinery embedded in the bacterial membrane, which is associated with many functions, such as stabilizing other Sec translocon components within the membrane, maintaining the transmembrane (TM) potential, and facilitating the ATP-independent stage of the translocation mechanism. Related studies suggest that SecDF undergoes functionally important conformational changes that involve mainly its P1-head domain and that these changes are coupled with the proton motive force (Δp)...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28636824/bicanonical-ab-initio-molecular-dynamics-for-open-systems
#11
Johannes Frenzel, Bernd Meyer, Dominik Marx
Performing ab initio molecular dynamics simulations of open systems, where the chemical potential rather than the number of both, nuclei and electrons is fixed, still is a challenge. Here, drawing on bicanonical sampling ideas introduced two decades ago by Swope and Andersen to calculate chemical potentials of liquids and solids, an ab initio simulation technique is devised, which introduces a fictitious dynamics of two superimposed but otherwise independent periodic systems including full electronic structure, such that either the chemical potential or the average fractional particle number of a specific chemical species can be kept constant...
June 21, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28634293/intrinsic-map-dynamics-exploration-for-uncharted-effective-free-energy-landscapes
#12
Eliodoro Chiavazzo, Roberto Covino, Ronald R Coifman, C William Gear, Anastasia S Georgiou, Gerhard Hummer, Ioannis G Kevrekidis
We describe and implement a computer-assisted approach for accelerating the exploration of uncharted effective free-energy surfaces (FESs). More generally, the aim is the extraction of coarse-grained, macroscopic information from stochastic or atomistic simulations, such as molecular dynamics (MD). The approach functionally links the MD simulator with nonlinear manifold learning techniques. The added value comes from biasing the simulator toward unexplored phase-space regions by exploiting the smoothness of the gradually revealed intrinsic low-dimensional geometry of the FES...
June 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28632421/novel-urushiol-derivatives-as-hdac8-inhibitors-rational-design-virtual-screening-molecular-docking-and-molecular-dynamics-studies
#13
Hao Zhou, Chengzhang Wang, Tao Deng, Ran Tao, Wenjun Li
Three series of novel urushiol derivatives were designed by introducing a hydroxamic acid moiety into the tail of an alkyl side chain and substituents with differing electronic properties or steric bulk onto the benzene ring and alkyl side chain. The compounds' binding affinity towards HDAC8 was screened by Glide docking. The highest-scoring compounds were processed further with molecular docking, MD simulations and binding free energy studies to analyze the binding modes and mechanisms. Ten compounds had Glide scores of -8...
June 20, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28628859/structural-and-functional-effects-of-nucleotide-variation-on-the-human-tb-drug-metabolizing-enzyme-arylamine-n-acetyltransferase-1
#14
Ruben Cloete, Wisdom A Akurugu, Cedric J Werely, Paul D van Helden, Alan Christoffels
The human arylamine N-acetyltransferase 1 (NAT1) enzyme plays a vital role in determining the duration of action of amine-containing drugs such as para-aminobenzoic acid (PABA) by influencing the balance between detoxification and metabolic activation of these drugs. Recently, four novel single nucleotide polymorphisms (SNPs) were identified within a South African mixed ancestry population. Modeling the effects of these SNPs within the structural protein was done to assess possible structure and function changes in the enzyme...
June 10, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28627969/identification-of-potential-inhibitors-of-fasciola-gigantica-thioredoxin1-computational-screening-molecular-dynamics-simulation-and-binding-free-energy-studies
#15
Rohit Shukla, Harish Shukla, Parismita Kalita, Amit Sonkar, Tripti Pandey, Dev Bukhsh Singh, Awanish Kumar, Timir Tripathi
Fasciola gigantica is the causative organism of fascioliasis and is responsible for major economic losses in livestock production globally. F. gigantica thioredoxin1 (FgTrx1) is an important redox-active enzyme involved in maintaining the redox homeostasis in the cell. To identify a potential anti-fasciolid compound, we conducted a structure-based virtual screening of natural compounds from the ZINC database (n = 1,67,740) against the FgTrx1 structure. The ligands were docked against FgTrx1 and 309 ligands were found to have better docking score...
June 19, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28627890/improved-description-of-sulfur-charge-anisotropy-in-opls-force-fields-model-development-and-parameterization
#16
Xin Cindy Yan, Michael J Robertson, Julian Tirado-Rives, William L Jorgensen
The atomic point-charge model used in most molecular mechanics force fields does not represent well the electronic anisotropy that is featured in many directional non-covalent interactions. Sulfur participates in several types of such interactions with its lone pairs and σ-holes. The current study develops new models, via the addition of off-atom charged sites, for a variety of sulfur compounds in the OPLS-AA and OPLS/CM5 force fields to address the lack of charge anisotropy. Parameter optimization is carried out to reproduce liquid-state properties, torsional and non-covalent energetics from reliable quantum mechanical calculations, and electrostatic potentials...
June 19, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28623599/energetics-and-reactivity-of-small-beryllium-deuterides
#17
Ivan Sukuba, Alexander Kaiser, Stefan E Huber, Jan Urban, Michael Probst
Enthalpies and free energies of reaction for small neutral and charged beryllium deuterides BeD, BeD2, and BeD3 that have been calculated are reported for a temperature range of 0 K to 1000 K. We discuss probable dissociation channels and possible ways of producing BeD by localizing the relevant transition states and by calculating corresponding rate constants. BeD and BeD(+) are found to be the most stable ones among the considered compounds. BeD2 and [Formula: see text] are more likely to decompose into Be(0,+) + D2 than into BeD(0,+) + D...
July 2017: Journal of Molecular Modeling
https://www.readbyqxmd.com/read/28623339/machine-learning-and-network-analysis-of-molecular-dynamics-trajectories-reveal-two-chains-of-red-ox-specific-residue-interactions-in-human%C3%A2-protein-disulfide-isomerase
#18
Razieh Karamzadeh, Mohammad Hossein Karimi-Jafari, Ali Sharifi-Zarchi, Hamidreza Chitsaz, Ghasem Hosseini Salekdeh, Ali Akbar Moosavi-Movahedi
The human protein disulfide isomerase (hPDI), is an essential four-domain multifunctional enzyme. As a result of disulfide shuffling in its terminal domains, hPDI exists in two oxidation states with different conformational preferences which are important for substrate binding and functional activities. Here, we address the redox-dependent conformational dynamics of hPDI through molecular dynamics (MD) simulations. Collective domain motions are identified by the principal component analysis of MD trajectories and redox-dependent opening-closing structure variations are highlighted on projected free energy landscapes...
June 16, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28622610/f1174v-mutation-alters-the-alk-active-conformation-in-response-to-crizotinib-in-nsclc-insight-from-molecular-simulations
#19
Fariba Dehghanian, Maryam Kay, Sadeq Vallian
Crizotinib is an efficient antineoplastic drug for treatment of non-small cell lung carcinoma (NSCLC), which is identified as an anaplastic lymphoma kinase (ALK) inhibitor. F1174V is a recently identified acquired point mutation relating to the Crizotinib resistance in NSCLC patients. The mechanism of Crizotinib resistance relating to F1174V mutation as a non-active site mutation remains unclear. In this study, the molecular dynamic simulation was used to investigate the possible mechanisms by which F1174V mutation may affect the structure and activity of ALK kinase domain...
June 8, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28622469/free-energy-calculations-of-microcin-j25-variants-binding-to-the-fhua-receptor
#20
Pin-Kuang Lai, Yiannis N Kaznessis
Computer simulations are performed to study the antimicrobial peptide microcin J25 (MJ25), a 21-mer peptide with an unusual lasso structure and high activity against Gram-negative bacteria. MJ25 has intracellular targets. The initial step for MJ25 acquisition in bacterial cells is binding to the outer membrane receptor FhuA. Molecular dynamics simulation is implemented to study the binding mechanism of MJ25 to FhuA and to search for important binding residues. The absolute binding free energy calculated from combined free energy perturbation (FEP) and thermodynamic integration (TI) methods agrees well with experimental data...
June 16, 2017: Journal of Chemical Theory and Computation
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