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Molecular dynamics simulation free energy

Sanjib Paul, Tanmoy Kumar Paul, Srabani Taraphder
The role of structure and dynamics of an enzyme has been investigated at three different stages of its function including the chemical event it catalyzes. A one-pot computational method has been designed for each of these stages based on classical and/or QM-MM molecular dynamics and transition path sampling simulations. For a pair of initial and final states A and B separated by a high free energy barrier, using a two-stage selection process, several collective variables (CVs) are identified that can delineate A and B...
February 21, 2018: Journal of Physical Chemistry. B
Tomonori Hayami, Kota Kasahara, Haruki Nakamura, Junichi Higo
An enhanced conformational sampling method is proposed: virtual-system coupled canonical molecular dynamics (VcMD). Although VcMD enhances sampling along a reaction coordinate, this method is free from estimation of a canonical distribution function along the reaction coordinate. This method introduces a virtual system that does not necessarily obey a physical law. To enhance sampling the virtual system couples with a molecular system to be studied. Resultant snapshots produce a canonical ensemble. This method was applied to a system consisting of two short peptides in an explicit solvent...
February 21, 2018: Journal of Computational Chemistry
Jian Gao, Li Liang, Qingqing Chen, Ling Zhang, Tonghui Huang
Acetyl-coenzyme A carboxylases (ACCs) is the first committed enzyme of fatty acid synthesis pathway. The inhibition of ACC is thought to be beneficial not only for diseases related to metabolism, such as type-2 diabetes, but also for infectious disease like bacterial infection disease. Soraphen A, a potent allosteric inhibitor of BC domain of yeast ACC, exhibit lower binding affinities to several yeast ACC mutants and the corresponding drug resistance mechanisms are still unknown. We report here a theoretical study of binding of soraphen A to wild type and yeast ACC mutants (including F510I, N485G, I69E, E477R, and K73R) via molecular dynamic simulation and molecular mechanics/generalized Born surface area free energy calculations methods...
February 20, 2018: Journal of Computer-aided Molecular Design
Koji Ogata, Makoto Hatakeyama, Shinichiro Nakamura
The octanol-water partition coefficient (log P ow ) is an important index for measuring solubility, membrane permeability, and bioavailability in the drug discovery field. In this paper, the log P ow values of 58 compounds were predicted by alchemical free energy calculation using molecular dynamics simulation. In free energy calculations, the atomic charges of the compounds are always fixed. However, they must be recalculated for each solvent. Therefore, three different sets of atomic charges were tested using quantum chemical calculations, taking into account vacuum, octanol, and water environments...
February 15, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Antenor Jose Paulista Neto, Eudes E Fileti
Molecular dynamics simulations were used to describe and quantify the role of edge groups on the hydrating properties of graphene oxide (GO). For this six different oxygen concentrations were investigated, and in four of them carboxyl groups were present. Structural analysis indicates a greater probability for the water solvation around the GO edges in detriment of the region of its basal plane while hydrogen bonding analyzes indicates that edge groups are very expressive, participating on about 60% of the total number of bonds...
February 20, 2018: Journal of Physical Chemistry. B
Patrick Bleiziffer, Kay Schaller, Sereina Riniker
Parametrization of small organic molecules for classical molecular dynamics simulations is not trivial. The vastness of the chemical space makes approaches using building blocks challenging. The most common approach is therefore an invidual parametrization of each compound by deriving partial charges from semi-empirical or ab initio calculations and inheriting the bonded and van der Waals (Lennard-Jones) parameters from a biomolecular force field. The quality of the partial charges generated in this fashion depends on the level of the quantum-chemical calculation as well as on the extraction procedure used...
February 20, 2018: Journal of Chemical Information and Modeling
Shilei Yan, Li Zhang, Shuai Wang, Tianhao Wu, Zhixin Gong
Spinal cord injury (SCI) is a severe disease associated with permanent neurological deficit. Recent studies in the treatment of SCI have demonstrated that the Ras/Raf/extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway serves an important role in the disease etiology, and that upregulation of this signaling pathway is associated with the development of SCI. In the present study, inhibition of Ras protein was employed in order to downregulate the Ras/Raf/ERK1/2 signaling pathway using compounds of natural origin from the Interbioscreen natural compound database...
March 2018: Experimental and Therapeutic Medicine
Bindu Madhuri Cavuturu, Vishwambar Vishnu Bhandare, Amutha Ramaswamy, Neelakantan Arumugam
By virtue of their regulatory role in the biological process, certain protein-protein complexes form potential targets for designing and discovery of drugs. Alteration set in the controlled formation of such complexes results in dysregulation of several metabolic processes, leading to diseased condition. β-catenin/Tcf4 complex is one such protein-protein complex found altered in colorectal epithelial cells resulting in activation of target genes leading to cancer. Recently certain lignans from seeds of the oil crop sesame were found inhibiting initiation and progression of this type of cancer...
February 18, 2018: Journal of Biomolecular Structure & Dynamics
Sonu Kumar, Piotr Cieplak
Posttranslational modifications that involve either reversible covalent modification of proteins or irreversible proteolysis are central to the regulation of key cellular mechanisms, including apoptosis, cell-cycle regulation and signal transduction. There is mounting evidence suggesting cross-talk between proteases and kinases. For instance: caspases, a class of proteases involved in programmed cell death-apoptosis, cleave a large set of various types of proteins. Simultaneously, kinases restrict caspase activity by phosphorylating their protein substrates in the vicinity of cleavage site...
February 16, 2018: Apoptosis: An International Journal on Programmed Cell Death
Weiwei Xue, Panpan Wang, Gao Tu, Fengyuan Yang, Guoxun Zheng, Xiaofeng Li, Xiaoxu Li, Yuzong Chen, Xiaojun Yao, Feng Zhu
Amitifadine, the only drug ever clinically tested in Phase 3 for treating depression, is a triple reuptake inhibitor (TRI) that simultaneously interacts with human monoamine transporters (MATs) including hSERT, hNET and hDAT. This novel multi-target strategy improves drug efficacy and reduces the toxic side effects of drugs. However, the binding modes accounting for amitifadine's polypharmacological mode of action are still elusive, and extensive exploration of the amitifadine-target interactions between amitifadine and MATs is urgently needed...
February 16, 2018: Physical Chemistry Chemical Physics: PCCP
Xin Wang, Kaimin Lu, Hao Luo, Danfeng Liang, Xin Long, Yuan Yuan, Chuanfang Wu, Jinku Bao
Liver X receptor (LXR), a member of the nuclear receptor superfamily, mainly serves as a reverse cholesterol transporter in lipid metabolism. It has been demonstrated that LXR is a promising target for the treatment of cardiovascular diseases. LXR is also involved in cancer metabolism, glucose homeostasis, immunity, and various physiological processes. The antitumor function of LXR has become of great interest to researchers in recent years. However, while it is believed that activating LXR with small molecules could be a promising approach to cancer treatment, effective drugs that target LXR are yet to be reported...
February 15, 2018: Journal of Molecular Modeling
Ryuma Sato, Ryuhei Harada, Yasuteru Shigeta
Photolyases (PHRs) and cryptochromes (CRYs) belong to the same family known as blue-light photoreceptors. Although their amino acid sequences and corresponding structures are similar to each other, they exert different functions. PHRs function as an enzyme to repair UV-induced deoxyribonucleic acid (DNA) lesions such as a cyclobutane pyrimidine dimer (CPD) and a (6-4) photoproduct ((6-4)pp), whereas CRYs are a circadian photoreceptor in plants and animals and at the same time they control the photoperiodic induction of flowering in plants...
2018: Biophysics and Physicobiology
Fan Zhao, Wei Jin, Lin Ma, Jian-Ye Zhang, Jin-Long Wang, Jing-Hai Zhang, Yong-Bo Song
Voltage-gated sodium (Na v ) channels play a pivotal role for the changes in membrane potential and belong to large membrane proteins that compose four voltage sensor domains (VSD1-4). In this study we describe the binding mode and selectivity of one of the aryl sulfonamide sodium channel inhibitors, PF-04856264, for the VSD4s in Na v 1.4, Na v 1.5 and Na v 1.7, respectively, through molecular dynamics simulation and enhanced post-dynamics analyses. Our results show that there are three binding site regions (BSR1-3) in the combination of the ligand and receptors, of which BSR1 and BSR3 contribute to the selectivity and affinity of the ligand to the receptor...
February 15, 2018: Journal of Biomolecular Structure & Dynamics
Noeman Ardalan, Sako Mirzaie, Abbas Akhavan Sepahi, Ramazan Ali Khavari-Nejad
L-Asparaginases (ASNase) belong to a family of amidohydrolases, have both asparaginase and glutaminase activity. Acute lymphocytic leukemia (ALL) is an outrageous disease worldwide. Bacterial ASNase has been used for the treatment of ALL. Glutaminase activity of enzyme causes some side effect and it is not essential for anticancer activity. The aim of this study was engineering of Escherichia coli asparaginase II to find a mutant with reduced glutaminase activity by molecular docking, molecular dynamics (MD) and QM-MM (Quantum mechanics molecular dynamics) simulations...
March 2018: Medical Hypotheses
Paul Grassein, Patrice Delarue, Harold Abraham Scheraga, Gia G Maisuradze, Patrick Senet
Protein folding/unfolding can be analysed experimentally at a local scale by monitoring the physical properties of local probes as a function of the temperature, as for example the distance between fluorophores or the values of chemical shifts of backbone atoms. Here, the analytical Lifson-Roig model for the helix-coil transition is modified to analyse local thermal unfolding of the fast-folder W protein of bacteriophage lambda (gpW) simulated by all-atom molecular dynamics (MD) simulations in explicit solvent at fifteen different temperatures...
February 15, 2018: Journal of Physical Chemistry. B
Viveca Lindahl, Pontus Gourdon, Magnus Andersson, Berk Hess
Aquaporin TIP2;1 is a protein channel permeable to both water and ammonia. The structural origin of ammonia selectivity remains obscure, but experiments have revealed that a double mutation renders it impermeable to ammonia without affecting water permeability. Here, we aim to reproduce and explain these observations by performing an extensive mutational study using microsecond long molecular dynamics simulations, applying the two popular force fields CHARMM36 and Amber ff99SB-ILDN. We calculate permeabilities and free energies along the channel axis for ammonia and water...
February 14, 2018: Scientific Reports
Juan Duan, Chuncai Hu, Jiafan Guo, Lianxian Guo, Jia Sun, Zuguo Zhao
The mechanism of substrate hydrolysis of New Delhi metallo-β-lactamase 1 (NDM-1) has been reported, but the process in which NDM-1 captures and transports the substrate into its active center remains unknown. In this study, we investigated the process of the substrate entry into the NDM-1 activity center through long unguided molecular dynamics simulations using meropenem as the substrate. A total of 550 individual simulations were performed, each of which for 200 ns, and 110 of them showed enzyme-substrate binding events...
February 14, 2018: Physical Chemistry Chemical Physics: PCCP
Alexander M Andrianov, Ivan A Kashyn, Alexander V Tuzikov
An integrated computational approach to in silico drug design was used to identify novel HIV-1 fusion inhibitor scaffolds mimicking broadly neutralizing antibody (bNab) 10E8 targeting the membrane proximal external region (MPER) of the HIV-1 gp41 protein. This computer-based approach included (i) generation of pharmacophore models representing 3D-arrangements of chemical functionalities that make bNAb 10E8 active towards the gp41 MPER segment, (ii) shape and pharmacophore-based identification of the 10E8-mimetic candidates by a web-oriented virtual screening platform pepMMsMIMIC, (iii) high-throughput docking of the identified compounds with the gp41 MPER peptide, and (iv) molecular dynamics simulations of the docked structures followed by binding free energy calculations...
January 15, 2018: Journal of Bioinformatics and Computational Biology
Kota Kasahara, Shun Sakuraba, Ikuo Fukuda
We investigate the problem of artifacts caused by the periodic boundary conditions (PBC) used in molecular simulation studies. Despite the long history of simulations with PBCs, the existence of measurable artifacts originating from PBCs applied to inherently non-periodic physical systems remains controversial. Specifically, these artifacts appear as differences between simulations of the same system but with different simulation-cell sizes. Earlier studies have implied that, even in the simple case of a small model peptide in water, sampling inefficiency is a major obstacle to understanding these artifacts...
February 13, 2018: Journal of Physical Chemistry. B
Marina A Kasimova, Aysenur Yazici, Yevgen Yudin, Daniele Granata, Michael L Klein, Tibor Rohacs, Vincenzo Carnevale
The non-selective cation channel TRPV1 is responsible for transducing noxious stimuli into action potentials propagating through peripheral nerves. It is activated by temperatures greater than 43 °C, while remaining completely non-conductive at temperatures lower than this threshold. The origin of this sharp response, which makes TRPV1 a biological temperature sensor, is not understood. Here we used molecular dynamics simulations and free energy calculations to characterize the molecular determinants of the transition between non-conductive and conductive states...
February 13, 2018: Journal of Physical Chemistry Letters
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