scholarly journals Temperature and Guanidine Hydrochloride effects on the folding thermodynamics of WW domain and variants

2021 ◽  
Author(s):  
Meng Qin ◽  
Zhenxing Liu ◽  
Wei Wang ◽  
D. Thirumalai
Keyword(s):  
Guanidine Hydrochloride ◽  
Transfer Model ◽  
Free Energies ◽  
Ww Domain ◽  
Molecular Transfer ◽  
Go Model ◽  
Β Sheet ◽  
Folding Thermodynamics ◽  
Good Agreement

We use simulations based on an all atom Go model to calculate the folding temperatures (Tfs) and free energies (ΔGs) of two variants of the WW domain, which is a small all β-sheet protein. The results, without adjusting any parameter, are in good agreement with experiments, thus validating the simulations. We then used the Molecular Transfer Model to predict the changes in their ΔG and Tfs as Guanidine Hydrochloride concentration is varied. The predictions can be readily tested in experiments.

scholarly journals Denaturants Alter the Flux through Multiple Pathways in the Folding of PDZ Domain

2017 ◽  
Author(s):  
Zhenxing Liu ◽  
D. Thirumalai
Keyword(s):  
Pdz Domain ◽  
Transfer Model ◽  
Guanidinium Chloride ◽  
Self Organized ◽  
Small Proteins ◽  
Molecular Transfer ◽  
Unfolded State ◽  
The Stability ◽  
Folding Thermodynamics ◽  
Good Agreement

AbstractAlthough we understand many aspects of how small proteins (number of residues less than about hundred) fold, it is a major challenge to understand how large proteins self-assemble. To partially overcome this challenge, we performed simulations using the Self-Organized Polymer model with Side Chains (SOP-SC) in guanidinium chloride (GdmCl), using the Molecular Transfer Model (MTM), to describe the folding of the 110-residue PDZ3 domain. The simulations reproduce the folding thermodynamics accurately including the melting temperature (Tm), the stability of the folded state with respect to the unfolded state. We show that the calculated dependence of ln kobs (kobs is the relaxation rate) has the characteristic Chevron shape. The slopes of the Chevron plots are in good agreement with experiments. We show that PDZ3 folds by four major pathways populating two metastable intermediates, in accord with the kinetic partitioning mechanism. The structure of one of the intermediates, populated after polypeptide chain collapse, is structurally similar to an equilibrium intermediate. Surprisingly, the connectivities between the intermediates and hence, the fluxes through the pathways depend on the concentration of GdmCl. The results are used to predict possible outcomes for unfolding of PDZ domain subject to mechanical forces. Our study demonstrates that, irrespective of the size or topology, simulations based on MTM and SOP-SC offer a framework for describing the folding of proteins, mimicking precisely the conditions used in experiments.

Partition Coefficients of Methylated DNA Bases Obtained from Free Energy Calculations with Molecular Electron Density Derived Atomic Charges.

2018 ◽  
Author(s):  
Alejandro Lara ◽  
Maximiliano Riquelme ◽  
Esteban Vöhringer-Martinez
Keyword(s):  
Electron Density ◽  
Partition Coefficients ◽  
Dna Bases ◽  
Atomic Charges ◽  
Free Energies ◽  
Solvation Model ◽  
Minimal Basis ◽  
Methylated Dna ◽  
Implicit Solvation Model ◽  
Good Agreement

<div> <div> <div> <p>Partition coefficients serve in various areas as pharmacology and environmental sciences to predict the hydrophobicity of different substances. Recently, they have been also used to address the accuracy of force fields for various organic compounds and specifically the methylated DNA bases. In this study atomic charges were derived by different partitioning methods (Hirshfeld and Minimal Basis Iterative Stockholder) directly from the electron density obtained by electronic structure calculations in vac- uum, with an implicit solvation model or with explicit solvation taking the dynamics of the solute and the solvent into account. To test the ability of these charges to describe electrostatic interactions in force fields for condensed phases the original atomic charges of the AMBER99 force field were replaced with the new atomic charges and combined with different solvent models to obtain the hydration and chloroform solvation free energies by molecular dynamics simulations. Chloroform-water partition coefficients derived from the obtained free energies were compared to experimental and previously reported values obtained with the GAFF or the AMBER-99 force field. The results show that good agreement with experimental data is obtained when the polarization of the electron density by the solvent has been taken into account deriving the atomic charges of polar DNA bases and when the energy needed to polarize the electron den- sity of the solute has been considered in the transfer free energy. These results were further confirmed by hydration free energies of polar and aromatic amino acid side chain analogues. Comparison of the two partitioning methods Hirsheld-I and Minimal Basis Iterative Stockholder (MBIS) revealed some deficiencies in the Hirshfeld-I method related to nonexistent isolated anionic nitrogen pro-atoms used in the method. Hydration free energies and partitioning coefficients obtained with atomic charges from the MBIS partitioning method accounting for polarization by the implicit solvation model are in good agreement with the experimental values. </p> </div> </div> </div>

THEORETICAL CALCULATION OF pKb VALUES FOR ANILINES AND SULFONAMIDE DRUGS IN AQUEOUS SOLUTION

2012 ◽  
Vol 11 (02) ◽  
pp. 283-295 ◽  
Author(s):  
BAHRAM GHALAMI-CHOOBAR ◽  
ALI GHIAMI-SHOMAMI ◽  
PARIA NIKPARSA
Keyword(s):  
Gas Phase ◽  
Continuum Model ◽  
Correlation Equation ◽  
Polarizable Continuum Model ◽  
Free Energies ◽  
Pcm Model ◽  
Solvation Models ◽  
Polarizable Continuum ◽  
Better Than ◽  
Good Agreement

In this work, calculations of p K b values have been performed for aniline and its substituted derivatives and sulfonamide drugs by using Gaussian 98 software package. Gas-phase energies were calculated with HF /6-31 G ** and B3LYP /6-31 G ** levels of theory. Free energies of solvation have been computed using the polarizable continuum model (PCM), conductor-like polarizable continuum model (CPCM) and the integral equation formalism-polarizable continuum model (IEFPCM) at the same levels which have been used for geometry determination in the gas-phase. The results show that the calculated p K b values using the B3LYP /6-31 G ** are better than those using the corresponding HF /6-31 G **. At first, the correlation equation was found to determine the p K b values of the investigated anilines. Then, this correlation equation was used to calculate the p K b values of the sulfonamide drugs. The results obtained indicate that the PCM model is a suitable solvation model for calculating p K b values in comparison to the other solvation models. For the investigated compounds a good agreement between the experimental and the calculated p K b values was also observed.

A Model for Predicting Temperature of Electrofusion Joints for Polyethylene Pipes

2009 ◽  
Vol 131 (6) ◽  
Author(s):  
Jianfeng Shi ◽  
Jinyang Zheng ◽  
Weican Guo ◽  
Ping Xu ◽  
Yongquan Qin ◽  
...  
Keyword(s):  
Thermal Contact ◽  
Power Input ◽  
Ultrasonic Test ◽  
Thermal Contact Conductance ◽  
Transfer Model ◽  
Contact Conductance ◽  
One Dimensional ◽  
Polyethylene Pipes ◽  
Heating Wire ◽  
Good Agreement

With the increasing application of electrofusion (EF) welding in connecting polyethylene (PE) pipes for gas distribution, more effort has been invested to ensure the safety of the pipeline systems. The objective of this paper is to investigate and understand the temperature distribution during EF welding. A one-dimensional transient heat-transfer model was proposed, taking the variation in the rate of power input, the phase transition of PE, and the thermal contact conductance between heating wire and PE into consideration. Then, experiments were designed to verify the power input and the temperature. The measured values of the power input were shown to be in good agreement with the analytical results. Based on ultrasonic test (UT), a new “Eigen-line” method was presented, which overcomes the difficulties found in the thermocouples’ temperature measurements. The results demonstrate good agreements between prediction and experiment. Finally, based on the presented model, a detailed parametric study was carried out to investigate the influences of the variation in the power input, the physical properties of PE, and the thermal contact conductance between heating wire and surrounding PE.

Heat Transfer in Grinding-Hardening of a Cylindrical Component

2011 ◽  
Vol 325 ◽  
pp. 35-41 ◽  
Author(s):  
Thai Nguyen ◽  
Liang Chi Zhang ◽  
Da Le Sun
Keyword(s):  
Heat Transfer ◽  
Three Dimensional ◽  
Hardened Layer ◽  
Transfer Model ◽  
Plunge Grinding ◽  
Cylindrical Component ◽  
Dimensional Finite Element ◽  
Three Dimensional Finite Element ◽  
Grinding Hardening ◽  
Good Agreement

A three-dimensional finite element heat transfer model incorporating a moving heat source was developed to investigate the heat transfer mechanism in grinding-hardening of a cylindrical component. The model was applied to analyze the grinding-hardening of quenchable steel 1045 by two grinding methods, traverse and plunge grinding. It was found that the heat generated can promote the martensitic phase transformation in the ground workpiece. As a result, a hardened layer with a uniform thickness can be produced by traverse grinding. However, the layer thickness generated by plunge grinding varies circumferentially. The results are in good agreement with the experimental observations.

scholarly journals A thermodynamic description of metastable c-TiAlZrN coatings with triple spinodally decomposed domains

2017 ◽  
Vol 53 (2) ◽  
pp. 85-93 ◽  
Author(s):  
J. Zhou ◽  
L. Zhang ◽  
L. Chen ◽  
Y. Du ◽  
Z.K. Liu
Keyword(s):  
Experimental Data ◽  
Phase Equilibria ◽  
First Principles ◽  
Thermodynamic Description ◽  
Quantitative Description ◽  
Experimental Phase Equilibria ◽  
Free Energies ◽  
Calphad Technique ◽  
Important Input ◽  
Good Agreement

A critical thermodynamic assessment of the metastable c-TiAlZrN coatings, which are reported to spinodally decompose into triple domains, i.e., c-TiN, c-AlN, and c-ZrN, was performed via the CALculation of PHAse Diagram (CALPHAD) technique based on the limited experimental data as well as the first-principles computed free energies. The metastable c-TiAlZrN coatings were modeled as a pseudo-ternary phase consisting of c-TiN, c-AlN and c-ZrN species, and described using the substitutional solution model. The thermodynamic descriptions for the three boundary binaries were directly taken from either the CALPHAD assessment or the first-principles results available in the literature except for a re-adjustment of the pseudo-binary c-AlN/c-ZrN system based on the experimental phase equilibria in the pseudo-ternary system. The good agreement between the calculated phase equilibria and the experimental data over the wide temperature range was obtained, validating the reliability of the presently obtained thermodynamic descriptions for the c-TiAlZrN system. Based on the present thermodynamic description, different phase diagrams and thermodynamic properties can be easily predicted. It is anticipated that the present thermodynamic description of the metastable c-TiAlZrN coatings can serve as the important input for the later quantitative description of the microstructure evolution during service life.

scholarly journals Novel Pyrazolo[3,4-c]pyridine Antagonists with Nanomolar affinity for A1 / A3 Adenosine Receptors: Binding Kinetics and Exploration of their Binding Profile Using Mutagenesis Experiments, MD simulations and TI/MD calculations

2021 ◽  
Author(s):  
Margarita Stampelou ◽  
Anna Suchankova ◽  
Eva Tzortzini ◽  
Lakshiv Dhingra ◽  
Kerry Barkan ◽  
...  
Keyword(s):  
Drug Design ◽  
Transmembrane Helix ◽  
Rank Correlation ◽  
Membrane System ◽  
Md Simulations ◽  
Dissociation Rate ◽  
The Novel ◽  
Free Energies ◽  
Electronegative Group ◽  
Good Agreement

Drugs targeting the four adenosine receptor (AR) subtypes can provide “soft" treatment of various significant diseases. Even for the two experimentally resolved AR subtypes the description of the orthosteric binding area and structure-activity relationships of ligands remains a demanding task due to the high similar amino acids sequence but also the broadness and flexibility of the ARs binding area. The identification of new pharmacophoric moieties and nanomolar leads and the exploration of their binding area with mutagenesis and state-of-the-art computational methods useful also for drug design purposes remains a challenging aim for all ARs. Here, we identified several low nanomolar ligands and potent competitive antagonists against A1R / A3R, containing the novel pyrazolo[3,4-c]pyridine pharmacophore for ARs, from a screen of an in-house library of only 52 compounds, originally designed for anti-proliferative activity. We identified L2-L10, A15, A17 with 3-aryl, 7-anilino and a electronegative group at 5-position as low micromolar to low nanomolar A1R / A3R antagonists. A17 has for A1R Kd = 5.62 nM and a residence time (RT) 41.33 min and for A3R Kd = 13.5 nM, RT = 47.23 min. The kinetic data showed that compared to the not potent or mediocre congeners the active compounds have similar association, for example at A1R Kon = 13.97 x106 M-1 (A17) vs Kon = 3.36 x106 M-1 (A26) but much lower dissociation rate Koff = 0.024 min-1 (A17) vs 0.134 min-1 (A26). Using molecular dynamics (MD) simulations and mutagenesis experiments we investigated the binding site of A17 showing that it can interact with an array of residues in transmembrane helix 5 (TM5), TM6, TM7 of A1R or A3R including residues E5.30, E5.28, T7.35 in A1R instead of Q5.28, V5.30 , L7.35 in A3R. A striking observation for drug design purposes is that for L2506.51A the binding affinity of A17 significantly increased at A1R. A17 provides a lead representative of a promising series and by means of the Thermodynamics Integration coupled with MD simulations (TI/MD) method, first applied here on whole GPCR- membrane system and showing a very good agreement between calculated and experimental relative binding free energies for A1R and A3R (spearman rank correlation p = 0.82 and 0.84, respectively), and kinetic experiments can lead to ligands with improved profile against ARs.

Heat Transfer Model and Analysis of Oil-Immersed Electrical Transformers with Heat Pipe Radiator

2012 ◽  
Vol 516-517 ◽  
pp. 312-315
Author(s):  
Guang Hua Li ◽  
Hong Lei Liu ◽  
De Jian Wang
Keyword(s):  
Heat Transfer ◽  
Numerical Simulation ◽  
Temperature Field ◽  
Heat Pipe ◽  
Heat Transfer Model ◽  
Transfer Model ◽  
Cooling Device ◽  
Transformer Design ◽  
Electrical Transformers ◽  
Good Agreement

This paper has formulated a heat transfer model for analyzing the cooling properties of a heat pipe cooling device of oil-immersed electrical transformer. Based on the model, the oil temperature field of a 30 KVA oil-immersed transformer has been numerical simulated, and experiments also had been conducted. Results showed that the numerical simulation has good agreement with experiment results. Results also showed that heat pipe radiator is feasible for oil-immersed electrical transformer cooling. The model can be used to analyze the oil temperature distribution properties in an oil-immersed electrical transformer with heat pipe cooling device, and provide theoretical guide for transformer design and improvement.

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