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Molecular dynamics simulation free energy

Denitsa Yordanova, Eric Ritter, Thomas Gerlach, Jan-Hendrik Jensen, Irina Smirnova, Sven Jakobtorweihen
The partition equilibria of solutes between micelles and an aqueous phase is a key factor in many applications. Depending on the task, many micelle-solute combinations are possible. Therefore, theoretical methods to predict the partition behavior in micellar systems are needed. Here, two predictive methods are evaluated and compared. First, it is shown how molecular dynamics simulations (MD) with the umbrella sampling method can be used to calculate free energy profiles in micellar systems. The second applied method is an extension of the COSMO-RS theory to anisotropic systems termed COSMOmic...
May 23, 2017: Journal of Physical Chemistry. B
Ritaban Halder, Rabindra Nath Manna, Sandipan Chakraborty, Biman Jana
Large scale conformational transition from open to closed state of adenylate kinase (ADK) is essential for its catalytic cycle. Apo-ADK undergoes conformational transition in such a way that closely resembles open to closed conformational transition. Here, equilibrium simulations, free energy simulations, QM/MM calculations in combination with several bioinformatics approaches have been used to explore the molecular origin of this conformational transition in apo-ADK. Apart from its conventional open state, E...
May 23, 2017: Journal of Physical Chemistry. B
Junmin Yu, Shilei Wang, Junjie Yu, Chuansheng Liu, Fenghe Xu, Shijie Wang, Yusheng Yi, Yanwei Yin
The troponin (Tn) is a ternary complex consisting of three subunits TnC, TnI and TnT; molecular disruption of the Tn complex has been recognized as an attractive strategy against neuropathic pain. Here, a self-inhibitory peptide is stripped from the switch region of TnI interaction interface with TnC, which is considered as a lead molecular entity and then used to generate potential peptide disruptors of TnC-TnI interaction based on a rational molecular design protocol. The region is a helical peptide segment capped by N- and C-terminal disorders...
May 3, 2017: Bioorganic Chemistry
Zahra Dolatkhah, Shahrzad Javanshir, Ahmad Shahir Sadr, Jaber Hosseini, Soroush Sardari
A series of 4H-chromone-1,2,3,4-tetrahydropyrimidine-5-carboxylates derivatives were synthesized via a three component one-pot condensation of chromone-3-carbaldehyde, alkyl acetoacetate, and urea or thiourea, using MCM-41-SO3H as efficient nanocatalysts and evaluated for their anticancer activity using a combined in silico docking and molecular dynamics protocol to estimate the binding affinity of the title compounds with the Bcr-Abl oncogene. Two programs, AutoDock 4 and AutoDock Vina software were applied to dock the target protein with synthesized compounds and ATP...
May 19, 2017: Journal of Chemical Information and Modeling
Manish Kesherwani, Sriram Raghavan, Krishnasamy Gunasekaran, Devadasan Velmurugan
Nicotinamide Phosphoribosyltransferase (NAMPT) is a rate-limiting enzyme in the biosynthesis of NAD. Cancer cells have elevated poly [ADP-Ribose] polymerase 1 (PARP) activity as well as the immense necessity of ATP: thereby consuming NAD at a higher rate than normal tissues. The perturbation of these intracellular processes is more sensitive and highly dependent on NAMPT to maintain the required NAD levels. Functional inhibition of NAMPT is, therefore, a promising drug target in therapeutic oncology. In this study, the importance of intermolecular contacts was realized based on contact occupancy and favorable energetic from molecular dynamic simulation to discern non-critical contacts of four different classes of potential NAMPT inhibitor bound complexes...
May 17, 2017: Journal of Biomolecular Structure & Dynamics
Tigran M Abramyan, David L Hyde-Volpe, Steven J Stuart, Robert A Latour
The use of standard molecular dynamics simulation methods to predict the interactions of a protein with a material surface have the inherent limitations of lacking the ability to determine the most likely conformations and orientations of the adsorbed protein on the surface and to determine the level of convergence attained by the simulation. In addition, standard mixing rules are typically applied to combine the nonbonded force field parameters of the solution and solid phases the system to represent interfacial behavior without validation...
May 17, 2017: Biointerphases
Dominik Sidler, Michael Cristofol Clough, Sereina Riniker
Replica-exchange enveloping distribution sampling (RE-EDS) allows the efficient estimation of free-energy differences between multiple end-states from a single molecular dynamics (MD) simulation. In EDS, a reference state is sampled, which can be tuned by two kinds of parameters, i.e. smoothness parameters(s) and energy offsets, such that all end-states are sufficiently sampled. The choice of these parameters is, however, not trivial. Replica exchange (RE) or parallel tempering is a widely applied technique to enhance sampling...
May 16, 2017: Journal of Chemical Theory and Computation
Karol Kulasinski
The diffusion coefficient of water adsorbed in hydrophilic porous materials, such as non-crystalline cellulose, depends on water activity. Faster diffusion at higher water concentrations is observed in experimental and modeling studies. In this paper, two asymptotic water concentrations, near-vacuum and fully saturated, are investigated at the surface of crystalline cellulose with molecular dynamics simulations. An increasing water concentration leads to significant changes in the free energy landscape due to perturbation of local electrostatic potential...
May 16, 2017: Langmuir: the ACS Journal of Surfaces and Colloids
Mathieu Salanne, Sami Tazi, Rodolphe Vuilleumier, Benjamin Rotenberg
We investigate the dissociation of a Ca$^{2+}$-Cl$^-$ pair in water using classical molecular dynamics simulations with a polarizable interaction potential, parameterized from ab initio calculations. By computing the potential of mean force as a function not only of the interionic distance but also of the coordination numbers by water molecules, we show it is necessary to use a collective variable describing the cation hydration in order to capture the dissociation mechanism. In the contact ion pair, the Ca$^{2+}$ cation has a first coordination sphere containing 5 or 6 water molecules...
May 16, 2017: Chemphyschem: a European Journal of Chemical Physics and Physical Chemistry
Omid Zarei, Maryam Hamzeh-Mivehroud, Silvia Benvenuti, Fulya Ustun-Alkan, Siavoush Dastmalchi
Purpose: Implication of protein-protein interactions (PPIs) in development of many diseases such as cancer makes them attractive for therapeutic intervention and rational drug design. RON (Recepteur d'Origine Nantais) tyrosine kinase receptor has gained considerable attention as promising target in cancer therapy. The activation of RON via its ligand, macrophage stimulation protein (MSP) is the most common mechanism of activation for this receptor. The aim of the current study was to perform in silico alanine scanning mutagenesis and to calculate binding energy for prediction of hot spots in protein-protein interface between RON and MSPβ chain (MSPβ)...
April 2017: Advanced Pharmaceutical Bulletin
Yaozong Li, Kwangho Nam
Despite the importance of kinases' catalytic activity regulation in cell signaling, detailed mechanisms underlying their activity regulation are poorly understood. Herein, using insulin-like growth factor 1 receptor kinase (IGF-1RK) as a model, the mechanisms of kinase regulation by its activation loop (A-loop) phosphorylation were investigated through molecular dynamics (MD) and alchemical free energy simulations. Analyses of the simulation results and free energy landscapes determined for the entire catalytic cycle of the kinase revealed that A-loop phosphorylation affects each step in the IGF-1RK catalytic cycle, including conformational change, substrate binding/product release and catalytic phosphoryl transfer...
May 1, 2017: Chemical Science
Sanat Kumar Tiwari, Nathaniel R Shaffer, Scott D Baalrud
The pressure and internal energy of an ultracold plasma in a state of quasiequilibrium are evaluated using classical molecular dynamics simulations. Coulomb collapse is avoided by modeling electron-ion interactions using an attractive Coulomb potential with a repulsive core. We present a method to separate the contribution of classical bound states, which form due to recombination, from the contribution of free charges when evaluating these thermodynamic state variables. It is found that the contribution from free charges is independent of the choice of repulsive core length scale when it is sufficiently short-ranged...
April 2017: Physical Review. E
Rajeswari Appadurai, Sanjib Senapati
HIV-1 protease is an important drug target for AIDS therapy. Nearly ten small molecule drugs have been approved by FDA. However, prolonged usage of these drugs produced protease mutants that are insusceptible to many of these drugs. The mutated proteases however continue to cleave the substrate peptides and thus remain largely functional. This poses a major challenge in the treatment strategies. Thus it has become imperative to understand how these mutations induce drug resistance while maintaining the enzymatic activity of this protein...
May 15, 2017: Biochemistry
Miroslav Krepl, Markus Blatter, Antoine Cléry, Fred F Damberger, Frédéric H T Allain, Jiri Sponer
The Fox-1 RNA recognition motif (RRM) domain is an important member of the RRM protein family. We report a 1.8 Å X-ray structure of the free Fox-1 containing six distinct monomers. We use this and the nuclear magnetic resonance (NMR) structure of the Fox-1 protein/RNA complex for molecular dynamics (MD) analyses of the structured hydration. The individual monomers of the X-ray structure show diverse hydration patterns, however, MD excellently reproduces the most occupied hydration sites. Simulations of the protein/RNA complex show hydration consistent with the isolated protein complemented by hydration sites specific to the protein/RNA interface...
May 13, 2017: Nucleic Acids Research
Pan Gao, Yinglu Cui, Rongling Wu
Cytochrome P450 14α-sterol demethylase (CYP51), the key enzyme in sterol biosynthesis pathway, is an important target protein of cholesterol-lowering agents, antifungal drugs and herbicides. CYP51B enzyme is one of the CYP51 family members. In the present study, we have chosen four representative inhibitors of CYP51B: diniconazole(Din), fluconazole(Flu), tebuconazole(Teb), voriconazole(Vor) and launched to investigate the binding features of CYP51B-inhibitor and gating characteristics via molecular docking and molecular dynamics(MD) simulations...
May 13, 2017: Journal of Biomolecular Structure & Dynamics
Ismail Erol, Busecan Aksoydan, Isik Kantarcioglu, Ramin E Salmas, Serdar Durdagi
The serotonin (5-hydroxytryptamine, 5HT) transporter (SERT) is a member of neurotransmitter sodium symporter (NSS) family, which maintains neurotransmitter by reuptaking 5HT into synapses. Decrease in serotonin concentrations in synaptic clefts have been reported to cause psychological and neurological disorders. Therefore, inhibition of SERT is a potent strategy for the treatment of related diseases such as depression. In this study, approximately 260,000 small molecules from an available chemical database have been virtually screened both at central and allosteric binding sites of SERT to identify potent novel candidate SERT inhibitors...
March 22, 2017: Journal of Molecular Graphics & Modelling
Maryam Farrokhnia, Karim Mahnam
Zoanthamine-type alkaloids display a wide spectrum of biological effects. This study aimed to examine the inhibitory effects of norzoanthamine and its ten homologues of zoanthamine class on human fibroblast collagenase by modeling a three-dimensional structure of the ligands at collagenase using energy minimization, docking, molecular dynamics simulation and MM-PB/GBSA binding free energy calculations. The results showed that zoanthamide, zooxathellamine and enol-iminium form of norzoanthamine, with lower binding free energies than other compounds, are potent inhibitors of collagenase...
2017: Iranian Journal of Pharmaceutical Research: IJPR
Kento Kasahara, Hiroshi Nakano, Hirofumi Sato
Carbon monoxide generation reaction of vinylene carbonate (VC) in the electrolyte solution of lithium ion batteries (ethylene carbonate (EC) and 1.0 M LiClO4/EC) is studied using the RISM-SCF-SEDD method, a hybrid methodology of statistical mechanics for molecular liquids and quantum chemistry. The analytical treatment of the solvent and lithium salt enables us to treat the complicated composition of the solution such as the concentration of the salt which is difficult for the methods based on the molecular dynamics (MD) simulation...
May 11, 2017: Journal of Physical Chemistry. B
Peng Cheng, Jiaojiao Li, Juan Wang, Xiaoyun Zhang, Honglin Zhai
Focal adhesion kinase (FAK) is one kind of tyrosine kinases that modulates integrin and growth factor signaling pathways, which is a promising therapeutic target because of involving in cancer cell migration, proliferation and survival. To investigate the mechanism between FAK and triazinic inhibitors and design high activity inhibitors, a molecular modeling integrated with 3D-QSAR, molecular docking, molecular dynamics simulations and binding free energy calculations was performed. The optimum CoMFA and CoMSIA modeles showed good reliability and satisfactory predictability (with Q(2)=0...
May 10, 2017: Journal of Biomolecular Structure & Dynamics
Liel Sapir, Daniel Harries
In processes involving aqueous solutions and in almost every biomolecular interaction, hydrogen bonds play important roles. Though weak compared to the covalent bond, hydrogen bonds modify the stability and conformation of numerous small and large molecules and modulate their intermolecular interactions. We propose a simple methodology for extracting hydrogen bond strength from atomistic level simulations. The free energy associated with hydrogen bond formation is conveniently calculated as the reversible work required to reshape a completely random pair probability distribution reference state into the one found in simulations where hydrogen bonds are formed...
May 10, 2017: Journal of Chemical Theory and Computation
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