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Molecular dynamics simulation free energy

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https://www.readbyqxmd.com/read/28107751/molecular-modeling-study-of-cp-690550-derivatives-as-jak3-kinase-inhibitors-through-combined-3d-qsar-molecular-docking-and-dynamics-simulation-techniques
#1
Jing Li Wang, Li Ping Cheng, Tian Chi Wang, Wei Deng, Fan Hong Wu
To develop more potent JAK3 kinase inhibitors, a series of CP-690550 derivatives were investigated using combined molecular modeling techniques, such as 3D-QSAR, molecular docking and molecular dynamics (MD). The leave-one-out correlation (q(2)) and non-cross-validated correlation coefficient (r(2)) of the best CoMFA model are 0.715 and 0.992, respectively. The q(2) and r(2) values of the best CoMSIA model are 0.739 and 0.995, respectively. The steric, electrostatic, and hydrophobic fields played important roles in determining the inhibitory activity of CP-690550 derivatives...
January 4, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28102071/temperature-induced-misfolding-in-prion-protein-evidences-of-multiple-partially-disordered-states-stabilized-by-non-native-hydrogen-bonds
#2
Neharika G Chamachi, Suman Chakrabarty
The structural basis of misfolding pathways of a cellular Prion (PrP(C)) into the toxic scrapie form (PrP(SC)) and identification of possible intermediates (e.g. PrP(*)) still eludes us. In this work, we have used a cumulative ~65µs of Replica Exchange Molecular Dynamics simulation data to construct the conformational free energy landscapes and capture the structural and thermodynamic characteristics associated with various stages of the thermal denaturation process in human Prion protein. The temperature dependent free energy surfaces consist of multiple metastable states stabilized by non-native contacts and hydrogen bonds, thus rendering the protein prone towards misfolding...
January 19, 2017: Biochemistry
https://www.readbyqxmd.com/read/28101966/the-free-energy-of-locking-a-ring-changing-a-deoxyribonucleoside-to-a-locked-nucleic-acid
#3
You Xu, Alessandra Villa, Lennart Nilsson
Locked nucleic acid (LNA), a modified nucleoside which contains a bridging group across the ribose ring, improves the stability of DNA/RNA duplexes significantly, and therefore is of interest in biotechnology and gene therapy applications. In this study, we investigate the free energy change between LNA and DNA nucleosides. The transformation requires the breaking of the bridging group across the ribose ring, a problematic transformation in free energy calculations. To address this, we have developed a 3-step (easy to implement) and a 1-step protocol (more efficient, but more complicated to setup), for single and dual topologies in classical molecular dynamics simulations, using the Bennett Acceptance Ratio method to calculate the free energy...
January 19, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28101951/rigidity-and-flexibility-in-the-tetrasaccharide-linker-of-proteoglycans-from-atomic-resolution-molecular-simulation
#4
Cathy Ng, Padmavathy Nandha Premnath, Olgun Guvench
Proteoglycans (PGs) are covalent conjugates between protein and carbohydrate (glycosaminoglycans). Certain classes of glycosaminoglycans such as chondroitin sulfate/dermatan sulfate and heparan sulfate utilize a specific tetrasaccharide linker for attachment to the protein component: GlcAβ1-3Galβ1-3Galβ1-4Xylβ1-O-Ser. Toward understanding the conformational preferences of this linker, the present work used all-atom explicit-solvent molecular dynamics (MD) simulations combined with Adaptive Biasing Force (ABF) sampling to determine high-resolution, high-precision conformational free energy maps ΔG(φ, ψ) for each glycosidic linkage between constituent disaccharides, including the variant where GlcA is substituted with IdoA...
January 19, 2017: Journal of Computational Chemistry
https://www.readbyqxmd.com/read/28100151/renin-inhibition-by-soyasaponin-i-a-potent-native-anti-hypertensive-compound
#5
Zeinab Tavassoli, Majid Taghdir, Bijan Ranjbar
One way to control hypertension is inactivation of the Renin- Angiotensin- Aldosterone System (RAAS). Inhibition of renin as a rate-limiting step of this system is an effective way to stop up RAAS. It has been proved that soyasaponin I, an herbal compound obtained from soybeans, has anti-hypertensive effect via renin inhibition, so it has the potential of being an anti-hypertensive drug. Herein, some theoretical approaches such as Docking Simulation, Molecular Dynamics (MD) Simulation and MMPBSA analysis have been used to study how soyasaponin I inhibits renin at the structural level...
January 19, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28095341/effect-of-the-r119g-mutation-on-human-p5cr-structure-and-its-interactions-with-nad-insights-derived-from-molecular-dynamics-simulation-and-free-energy-analysis
#6
Peng Sang, Yue-Hui Xie, Lin-Hua Li, Yu-Jia Ye, Wei Hu, Jing Wang, Wen Wan, Rui Li, Long-Jun Li, Lin-Ling Ma, Zhi Li, Shu-Qun Liu, Zhao-Hui Meng
Pyrroline-5-carboxylate reductase (P5CR), an enzyme with conserved housekeeping roles, is involved in the etiology of cutis laxa. While previous work has shown that the R119G point mutation in the P5CR protein is involved, the structural mechanism behind the pathology remains to be elucidated. In order to probe the role of the R119G mutation in cutis laxa, we performed molecular dynamics (MD) simulations, essential dynamics (ED) analysis, and Molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations on wild type (WT) and mutant P5CR-NAD complex...
January 5, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28094951/diabat-interpolation-for-polymorph-free-energy-differences
#7
Kartik Kamat, Baron Peters
Existing methods to compute free energy differences between polymorphs use harmonic approximations, advanced non-Boltzmann bias sampling techniques, and/or multistage free energy perturbations. This work demonstrates how Bennett's diabat interpolation method (J.Comp. Phys. 1976, 22, 245) can be combined with energy gaps from lattice switch Monte Carlo techniques (Phys. Rev. E 2001, 61, 906) to swiftly estimate polymorph free energy differences. The new method requires only two unbiased molecular dynamics simulations, one for each polymorph...
January 17, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28094372/theoretical-studies-on-fgfr-isoform-selectivity-of-fgfr1-fgfr4-inhibitors-by-molecular-dynamics-simulations-and-free-energy-calculations
#8
Weitao Fu, Lingfeng Chen, Zhe Wang, Yanting Kang, Chao Wu, Qinqin Xia, Zhiguo Liu, Jianmin Zhou, Guang Liang, Yuepiao Cai
The activation and overexpression of fibroblast growth factor receptors (FGFRs) are highly correlated with a variety of cancers. Most small molecule inhibitors of FGFRs selectively target FGFR1-3, but not FGFR4. Hence, designing highly selective inhibitors towards FGFR4 remains a great challenge because FGFR4 and FGFR1 have a high sequence identity. Recently, two small molecule inhibitors of FGFRs, ponatinib and AZD4547, have attracted huge attention. Ponatinib, a type II inhibitor, has high affinity towards FGFR1/4 isoforms, but AZD4547, a type I inhibitor of FGFR1, displays much reduced inhibition toward FGFR4...
January 17, 2017: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/28088576/lid-domain-plasticity-and-lipid-flexibility-modulate-enzyme-specificity-in-human-monoacylglycerol-lipase
#9
Laura Riccardi, Jose M Arencibia, Luca Bono, Andrea Armirotti, Stefania Girotto, Marco De Vivo
Human monoacylglycerol lipase (MAGL) is a membrane-interacting enzyme that generates pro-inflammatory signaling molecules. For this reason, MAGL inhibition is a promising strategy to treat pain, cancer, and neuroinflammatory diseases. MAGL can hydrolyze monoacylglycerols bearing an acyl chain of different lengths and degrees of unsaturation, cleaving primarily the endocannabinoid 2-arachidonoylglycerol. Importantly, the enzymatic binding site of MAGL is confined by a 75-amino-acid-long, flexible cap domain, named 'lid domain', which is structurally similar to that found in several other lipases...
January 11, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28088161/efficient-free-energy-calculations-by-combining-two-complementary-tempering-sampling-methods
#10
Liangxu Xie, Lin Shen, Zhe-Ning Chen, Mingjun Yang
Although energy barriers can be efficiently crossed in the reaction coordinate (RC) guided sampling, this type of method suffers from identification of the correct RCs or requirements of high dimensionality of the defined RCs for a given system. If only the approximate RCs with significant barriers are used in the simulations, hidden energy barriers with small to medium height would exist in other degrees of freedom (DOFs) relevant to the target process and consequently cause the problem of insufficient sampling...
January 14, 2017: Journal of Chemical Physics
https://www.readbyqxmd.com/read/28080057/identification-of-binding-modes-for-amino-naphthalene-2-cyanoacrylate-anca-probes-to-amyloid-fibrils-from-molecular-dynamics-simulations
#11
Huan He, Juan Xu, Dan-Yang Cheng, Li Fu, Yu-Shu Ge, Feng-Lei Jiang, Yi Liu
Amino naphthalene 2-Cyanoacrylate (ANCA) probe is a kind of fluorescent amyloid binding probe that can report a different fluorescence emission when bound to different types of amyloid deposits in tissue, while their interactions with amyloid fibrils remain unclear due to the insoluble nature of amyloid fibrils. Here, all atom molecular dynamics simulations were used to investigate the interaction between ANCA probes with three different amyloid fibrils. Two common binding modes of ANCA probes on Aβ40 amyloid fibrils were identified by cluster analysis of multiple simulations...
January 12, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28079371/a-binding-pose-flip-explained-via-enthalpic-and-entropic-contributions
#12
Michael Schauperl, Paul Czodrowski, Julian E Fuchs, Roland G Huber, Birgit J Waldner, Maren Podewitz, Christian Kramer, Klaus R Liedl
The anomalous binding modes of five highly similar fragments of TIE2 inhibitors, showing three distinct binding poses are investigated. We report a quantitative rationalization for the changes in binding pose based on molecular dynamics simulations. We investigated five fragments in complex with the transforming growth factor β receptor type 1 kinase domain. Analyses of these simulations using Grid Inhomogeneous Solvation Theory (GIST), pKA calculations, and a tool to investigate enthalpic differences upon binding unraveled the various thermodynamic contributions to the different binding modes...
January 12, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28078726/dissecting-the-cytochrome-p450-1a2-and-3a4-mediated-metabolism-of-aflatoxin-b1-in-ligand-and-protein-contributions
#13
Lars Olsen, Flemming S Jørgensen, Silvia Bonomo
Aflatoxin B1 (AFB1) is a chemically intriguing compound because it has several potential sites of metabolism (SOMs) while only some of them are observed experimentally. Cytochrome P450 (CYP) 3A4 and 1A2 are the major isoforms involved in its metabolism. Here, we systematically investigate reactivity and accessibility of all possible SOMs in these two CYPs to elucidate AFB1 metabolism. Density functional theory (DFT) calculations were used to determine activation energies for each possible reaction. Aliphatic hydroxylation on position 9A and 3α are energetically favored, whereas position 9 is the preferred site for epoxidation...
January 12, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28076845/molecular-dynamics-simulation-reveals-how-phosphorylation-of-tyrosine-26-of-phosphoglycerate-mutase-1-upregulates-glycolysis-and-promotes-tumor-growth
#14
Yan Wang, Wen-Sheng Cai, Luonan Chen, Guanyu Wang
Phosphoglycerate mutase 1 (PGAM1) catalyzes the eighth step of glycolysis and is often found upregulated in cancer cells. To test the hypothesis that the phosphorylation of tyrosine 26 residue of PGAM1 greatly enhances its activity, we performed both conventional and steered molecular dynamics simulations on the binding and unbinding of PGAM1 to its substrates, with tyrosine 26 either phosphorylated or not. We analyzed the simulated data in terms of structural stability, hydrogen bond formation, binding free energy, etc...
January 5, 2017: Oncotarget
https://www.readbyqxmd.com/read/28076816/mutation-g1629e-increases-von-willebrand-factor-cleavage-via-a-cooperative-destabilization-mechanism
#15
Camilo Aponte-Santamaría, Svenja Lippok, Judith J Mittag, Tobias Obser, Reinhard Schneppenheim, Carsten Baldauf, Frauke Gräter, Ulrich Budde, Joachim O Rädler
The large multimeric glycoprotein von Willebrand Factor (VWF) plays a pivotal adhesive role during primary hemostasis. VWF is cleaved by the protease ADAMTS13 as a down-regulatory mechanism to prevent excessive VWF-mediated platelet aggregation. For each VWF monomer, the ADAMTS13 cleavage site is located deeply buried inside the VWF A2 domain. External forces in vivo or denaturants in vitro trigger the unfolding of this domain, thereby leaving the cleavage site solvent-exposed and ready for cleavage. Mutations in the VWF A2 domain, facilitating the cleavage process, cause a distinct form of von Willebrand disease (VWD), VWD type 2A...
January 10, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28074360/exploring-the-stability-of-ligand-binding-modes-to-proteins-by-molecular-dynamics-simulations
#16
Kai Liu, Etsurou Watanabe, Hironori Kokubo
The binding mode prediction is of great importance to structure-based drug design. The discrimination of various binding poses of ligand generated by docking is a great challenge not only to docking score functions but also to the relatively expensive free energy calculation methods. Here we systematically analyzed the stability of various ligand poses under molecular dynamics (MD) simulation. First, a data set of 120 complexes was built based on the typical physicochemical properties of drug-like ligands. Three potential binding poses (one correct pose and two decoys) were selected for each ligand from self-docking in addition to the experimental pose...
January 10, 2017: Journal of Computer-aided Molecular Design
https://www.readbyqxmd.com/read/28071975/dynamics-of-fluoroquinolones-induced-resistance-in-dna-gyrase-of-mycobacterium-tuberculosis
#17
Bharati Pandey, Sonam Grover, Chetna Tyagi, Sukriti Goyal, Salma Jamal, Aditi Singh, Jagdeep Kaur, Abhinav Grover
DNA gyrase is a validated target of fluoroquinolones which are key components of multidrug resistance (MDR) TB treatment. Most frequent occurring mutations associated with high level of resistance to fluoroquinolone in clinical isolates of TB patients are A90V, D94G and A90V-D94G (double mutant), present in the larger subunit of DNA Gyrase. In order to explicate the molecular mechanism of drug resistance corresponding to these mutations, molecular dynamics and mechanics approach was applied. Structure based molecular docking of complex comprised of DNA bound with Gyrase A (large subunit) and Gyrase C (small subunit) with moxifloxacin revealed high binding affinity to wild type with considerably high Glide XP docking score of -7...
January 10, 2017: Journal of Biomolecular Structure & Dynamics
https://www.readbyqxmd.com/read/28068084/molecular-modeling-evaluation-of-the-enantiomers-of-a-novel-adenylyl-cyclase-2-inhibitor
#18
Neha Rana, Jason M Conley, Monica Soto-Velasquez, Francisco Leon, Stephen J Cutler, Val J Watts, Markus A Lill
Adenylyl cyclase 2 (AC2) is one of nine membrane-bound isoforms of adenylyl cyclase that converts ATP into cyclic AMP (cAMP), an important second messenger molecule. Up-regulation of AC2 is linked to cancers like pancreatic and small intestinal neuroendocrine tumors (NETs). The structures of the various isoforms of adenylyl cyclases are highly homologous, posing a significant challenge to drug discovery efforts for an effective, isoform-selective modulator of AC2. In a previous study, a screen identified a potential isoform-selective and non-competitive inhibitor of AC2, SKF83566...
January 9, 2017: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/28067527/probing-the-acid-induced-packing-structure-changes-of-the-molten-globule-domains-of-a-protein-near-equilibrium-unfolding
#19
Yi-Qi Yeh, Kuei-Fen Liao, Orion Shih, Ying-Jen Shiu, Wei-Ru Wu, Chun-Jen Su, Po-Chang Lin, U-Ser Jeng
Using simultaneously scanning small-angle X-ray scattering (SAXS) and UV-vis absorption with integrated online size exclusion chromatography, supplemental with molecular dynamics simulations, we unveil the long-postulated global structure evolution of a model multidomain protein bovine serum albumin (BSA) during acid-induced unfolding. Our results differentiate three global packing structures of the three molten globule domains of BSA, forming three intermediates I1, I2, and E along the unfolding pathway. The I1-I2 transition, overlooked in all previous studies, involves mainly coordinated reorientations across interconnected molten globule subdomains, and the transition activates a critical pivot domain opening of the protein for entering into the E form, with an unexpectedly large unfolding free energy change of -9...
January 19, 2017: Journal of Physical Chemistry Letters
https://www.readbyqxmd.com/read/28067516/elucidating-the-bacterial-membrane-disruption-mechanism-of-human-%C3%AE-defensin-5-a-theoretical-study
#20
Sang Won Jung, Juho Lee, Art E Cho
Human α-defensin 5 (HD5) is a broad-spectrum antibacterial peptide produced by small intestinal Paneth cells. Despite considerable experimental evidence for the correlation between bacterial membrane destruction and the antibacterial activity of HD5, its membrane disruption mechanism remains unclear. Using all-atom molecular dynamics (MD) simulations and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis, we demonstrate the membrane disruption mechanism of HD5 based on the intrinsic binding of HD5 to Gram-negative (GN) bacterial inner-membrane...
January 9, 2017: Journal of Physical Chemistry. B
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