scholarly journals Thermodynamic Insights of Base Flipping in TNA Duplex: Force Fields, Salt Concentrations, and Free Energy Simulation Methods

2020 ◽  
Author(s):  
Zhaoxi Sun ◽  
John Z. H. Zhang
Keyword(s):  
Free Energy ◽  
Phase Space ◽  
Force Field ◽  
Energy Barrier ◽  
Force Fields ◽  
Computational Modelling ◽  
High Energy ◽  
Energy Simulation ◽  
Free Energy Barrier ◽  
Base Flipping

<p>Threofuranosyl nucleic acid (TNA) is an analogue of DNA. Its inter-nucleotide linkages are shifted from the wild-type 5'-to-3' one to the 3'-to-2' one. As a result, the number of covalent bonds between consecutive phosphates is reduced from 6 to 5. This leads to higher chemical stability, less reactive groups, and lower conformational flexibility. Experimental observations indicate that the interaction network is perturbed at the minimal level and the thermodynamic stability of the duplex is unaltered upon the TNA mutation. Whether computational modelling could reproduce this result will be studied in the base flipping of the middle T (DNA) residue or its T-to-TFT mutation (TNA). We applied the equilibrium free energy simulation and the nonequilibrium stratification method proposed previously in the base flipping case, proving the applicability of alternative free energy simulation protocols. As the force field is the main accuracy-limiting factor when converged phase space sampling is obtained, we benchmarked three popular AMBER force fields for nucleotides. The last-generation force fields include bsc1 and OL15, both of which perform similarly in reproducing the structures near the crystal conformation in previous benchmark studies. Our results indicate that all these three force fields provide similar descriptions of the base-paired state. However, with free energy simulation constructing the free energy profiles along the conformational change pathway, high-energy regions are explored and these three force fields behave differently. The bsc1 force field is found to perform best in reproducing the similarity of stabilities of DNA and TNA duplexes. The free energy barrier of base flipping under the OL15 force field is lowered modestly in TNA, and thus this force field is also usable. However, the bsc0 force field provides wrong results. The TNA duplex is significantly less stable than the DNA duplex. Therefore, the bsc0 force field is not recommended in any application in modern nucleotide simulations. The salt concentration in nucleotide simulations is another factor influencing the thermodynamics of the system. Previous reports conclude that the net-neutral and excess-salt simulations provide similar results. However, the simulation method limits the phase space region explored in previous computational modelling. Our free energy simulation explores high-energy regions, where the excess salt does affect the thermodynamic stability. The free energy barrier along the base flipping pathway is generally elevated upon the addition of excess salts, but the relative height of the free energy barriers in DNA and TNA duplexes is not significantly changed. This phenomenon emphasizes the importance of adding sufficient salts to reproduce the experimental condition. </p>

scholarly journals Thermodynamic Insights of Base Flipping in TNA Duplex: Force Fields, Salt Concentrations, and Free Energy Simulation Methods

2020 ◽  
Author(s):  
Zhaoxi Sun ◽  
John Z. H. Zhang
Keyword(s):  
Free Energy ◽  
Phase Space ◽  
Force Field ◽  
Energy Barrier ◽  
Force Fields ◽  
Computational Modelling ◽  
High Energy ◽  
Energy Simulation ◽  
Free Energy Barrier ◽  
Base Flipping

<p>Threofuranosyl nucleic acid (TNA) is an analogue of DNA. Its inter-nucleotide linkages are shifted from the wild-type 5'-to-3' one to the 3'-to-2' one. As a result, the number of covalent bonds between consecutive phosphates is reduced from 6 to 5. This leads to higher chemical stability, less reactive groups, and lower conformational flexibility. Experimental observations indicate that the interaction network is perturbed at the minimal level and the thermodynamic stability of the duplex is unaltered upon the TNA mutation. Whether computational modelling could reproduce this result will be studied in the base flipping of the middle T (DNA) residue or its T-to-TFT mutation (TNA). We applied the equilibrium free energy simulation and the nonequilibrium stratification method proposed previously in the base flipping case, proving the applicability of alternative free energy simulation protocols. As the force field is the main accuracy-limiting factor when converged phase space sampling is obtained, we benchmarked three popular AMBER force fields for nucleotides. The last-generation force fields include bsc1 and OL15, both of which perform similarly in reproducing the structures near the crystal conformation in previous benchmark studies. Our results indicate that all these three force fields provide similar descriptions of the base-paired state. However, with free energy simulation constructing the free energy profiles along the conformational change pathway, high-energy regions are explored and these three force fields behave differently. The bsc1 force field is found to perform best in reproducing the similarity of stabilities of DNA and TNA duplexes. The free energy barrier of base flipping under the OL15 force field is lowered modestly in TNA, and thus this force field is also usable. However, the bsc0 force field provides wrong results. The TNA duplex is significantly less stable than the DNA duplex. Therefore, the bsc0 force field is not recommended in any application in modern nucleotide simulations. The salt concentration in nucleotide simulations is another factor influencing the thermodynamics of the system. Previous reports conclude that the net-neutral and excess-salt simulations provide similar results. However, the simulation method limits the phase space region explored in previous computational modelling. Our free energy simulation explores high-energy regions, where the excess salt does affect the thermodynamic stability. The free energy barrier along the base flipping pathway is generally elevated upon the addition of excess salts, but the relative height of the free energy barriers in DNA and TNA duplexes is not significantly changed. This phenomenon emphasizes the importance of adding sufficient salts to reproduce the experimental condition. </p>

scholarly journals High Throughput Virtual Screening of 230 Billion Molecular Solar Heat Battery Candidates

2020 ◽  
Author(s):  
Mads Koerstz ◽  
Anders S. Christensen ◽  
Kurt V. Mikkelsen ◽  
Mogens Brøndsted Nielsen ◽  
Jan H. Jensen
Keyword(s):  
Free Energy ◽  
Energy Barrier ◽  
Storage Capacity ◽  
Chemical Reactivity ◽  
Methodological Approach ◽  
Parent Compound ◽  
High Energy ◽  
Back Reaction ◽  
Free Energy Barrier ◽  
Practical Applications

<div> <div> <div> <div> <p>The dihydroazulene/vinylheptafulvene (DHA/VHF) thermocouple is a promising candidate for thermal heat batteries that absorb and store solar energy as chemical energy without the need for insulation. However, in order to be viable the energy storage capacity and lifetime of the high energy form (i.e. the free energy barrier to the back reaction) of the canonical parent compound must be increased significantly to be of practical use. We use semiempirical quantum chemical methods, machine learning, and density func- tional theory to virtually screen over 230 billion substituted DHA molecules to identify promising candidates. We identify a molecule with a predicted energy density of 0.38 kJ/g, which is significantly larger than the 0.14 kJ/g computed for the parent compound. The free energy barrier to the back reaction is 11 kJ/mol higher than the parent com- pound, which should correspond to a half-life of about 10 days - 4 months. This is considerably longer than the 3-39 hours (depending on solvent) observed for the parent compound and sufficiently long for many practical applications. Our paper makes two main important contributions: 1) a novel and generally applicable methodological approach that makes screening of huge libraries for properties involving chemical reactivity with modest computational resources, and 2) a clear demonstration that the storage capacity of the DHA/VHF thermocouple cannot be increased to >0.5 kJ/g by combining simple substituents. </p> </div> </div> </div><br></div>

scholarly journals High throughput virtual screening of 230 billion molecular solar heat battery candidates

2021 ◽  
Vol 3 ◽  
pp. e16
Author(s):  
Mads Koerstz ◽  
Anders S. Christensen ◽  
Kurt V. Mikkelsen ◽  
Mogens Brøndsted Nielsen ◽  
Jan H. Jensen
Keyword(s):  
Free Energy ◽  
Energy Barrier ◽  
Density Functional ◽  
Storage Capacity ◽  
Chemical Reactivity ◽  
Methodological Approach ◽  
Parent Compound ◽  
High Energy ◽  
Back Reaction ◽  
Free Energy Barrier

The dihydroazulene/vinylheptafulvene (DHA/VHF) thermocouple is a promising candidate for thermal heat batteries that absorb and store solar energy as chemical energy without the need for insulation. However, in order to be viable the energy storage capacity and lifetime of the high energy form (i.e., the free energy barrier to the back reaction) of the canonical parent compound must be increased significantly to be of practical use. We use semiempirical quantum chemical methods, machine learning, and density functional theory to virtually screen over 230 billion substituted DHA molecules to identify promising candidates. We identify a molecule with a predicted energy density of 0.38 kJ/g, which is significantly larger than the 0.14 kJ/g computed for the parent compound. The free energy barrier to the back reaction is 11 kJ/mol higher than the parent compound, which should correspond to a half-life of about 10 days—4 months. This is considerably longer than the 3–39 h (depending on solvent) observed for the parent compound and sufficiently long for many practical applications. Our paper makes two main important contributions: (1) a novel and generally applicable methodological approach that makes screening of huge libraries for properties involving chemical reactivity with modest computational resources, and (2) a clear demonstration that the storage capacity of the DHA/VHF thermocouple cannot be increased to >0.5 kJ/g by combining simple substituents.

scholarly journals High Throughput Virtual Screening of 230 Billion Molecular Solar Heat Battery Candidates

2020 ◽  
Author(s):  
Mads Koerstz ◽  
Anders S. Christensen ◽  
Kurt V. Mikkelsen ◽  
Mogens Brøndsted Nielsen ◽  
Jan H. Jensen
Keyword(s):  
Free Energy ◽  
Energy Barrier ◽  
Density Functional ◽  
Parent Compound ◽  
High Energy ◽  
Back Reaction ◽  
Free Energy Barrier ◽  
Functional Theory ◽  
Practical Applications ◽  
Quantum Chemical Methods

<div>The dihydroazulene/vinylheptafulvene (DHA/VHF) thermocouple is a promising can- didate for thermal heat batteries that absorb and store solar energy as chemical energy without the need for insulation. However, in order to be viable the energy storage capacity and lifetime of the high energy form (i.e. the free energy barrier to the back reaction) of the canonical parent compound must be increased significantly to be of practical use. We use semiempirical quantum chemical methods, machine learning, and density functional theory to virtually screen over 230 billion substituted DHA molecules to identify promis- ing candidates. We identify a molecule with a predicted energy density of 0.38 kJ/g, which is significantly larger than the 0.14 kJ/g computed for the parent compound. The free energy barrier to the back reaction is 11 kJ/mol higher than the parent compound, which should correspond to a half-life of about 10 days - 4 months. This is considerably longer than the 3-39 hours (depending on solvent) observed for the parent compound and sufficiently long for many practical applications. However, the main conclusion of this study is that there are no molecules among the 230 billion with a storage density approaching 1 kJ/g.<br></div>

scholarly journals High Throughput Virtual Screening of 230 Billion Molecular Solar Heat Battery Candidates

2020 ◽  
Author(s):  
Mads Koerstz ◽  
Anders S. Christensen ◽  
Kurt V. Mikkelsen ◽  
Mogens Brøndsted Nielsen ◽  
Jan H. Jensen
Keyword(s):  
Free Energy ◽  
Energy Barrier ◽  
Density Functional ◽  
Parent Compound ◽  
High Energy ◽  
Back Reaction ◽  
Free Energy Barrier ◽  
Functional Theory ◽  
Practical Applications ◽  
Quantum Chemical Methods

<div>The dihydroazulene/vinylheptafulvene (DHA/VHF) thermocouple is a promising can- didate for thermal heat batteries that absorb and store solar energy as chemical energy without the need for insulation. However, in order to be viable the energy storage capacity and lifetime of the high energy form (i.e. the free energy barrier to the back reaction) of the canonical parent compound must be increased significantly to be of practical use. We use semiempirical quantum chemical methods, machine learning, and density functional theory to virtually screen over 230 billion substituted DHA molecules to identify promis- ing candidates. We identify a molecule with a predicted energy density of 0.38 kJ/g, which is significantly larger than the 0.14 kJ/g computed for the parent compound. The free energy barrier to the back reaction is 11 kJ/mol higher than the parent compound, which should correspond to a half-life of about 10 days - 4 months. This is considerably longer than the 3-39 hours (depending on solvent) observed for the parent compound and sufficiently long for many practical applications. However, the main conclusion of this study is that there are no molecules among the 230 billion with a storage density approaching 1 kJ/g.<br></div>

Determination of Base Flipping Free Energy Landscapes from Nonequilibrium Stratification

2019 ◽  
Author(s):  
Xiaohui Wang ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Sampling Technique ◽  
Umbrella Sampling ◽  
Energy Simulation ◽  
Nonlinear Dependence ◽  
Free Energy Landscape ◽  
Convergence Criterion ◽  
Base Flipping ◽  
Convergence Behavior

<p>Correct calculation of the variation of free energy upon base flipping is crucial in understanding the dynamics of DNA systems. The free energy landscape along the flipping pathway gives the thermodynamic stability and the flexibility of base-paired states. Although numerous free energy simulations are performed in the base flipping cases, no theoretically rigorous nonequilibrium techniques are devised and employed to investigate the thermodynamics of base flipping. In the current work, we report a general nonequilibrium stratification scheme for efficient calculation of the free energy landscape of base flipping in DNA duplex. We carefully monitor the convergence behavior of the equilibrium sampling based free energy simulation and the nonequilibrium stratification and determine the empirical length of time blocks required for converged sampling. Comparison between the performances of equilibrium umbrella sampling and nonequilibrium stratification is given. The results show that nonequilibrium free energy simulation is able to give similar accuracy and efficiency compared with the equilibrium enhanced sampling technique in the base flipping cases. We further test a convergence criterion we previously proposed and it comes out that the convergence behavior determined by this criterion agrees with those given by the time-invariant behavior of PMF and the nonlinear dependence of standard deviation on the sample size. </p>

DFT study on the hydrolysis of metsulfuron-methyl: A sulfonylurea herbicide

2018 ◽  
Vol 17 (08) ◽  
pp. 1850050 ◽  
Author(s):  
Qiuhan Luo ◽  
Gang Li ◽  
Junping Xiao ◽  
Chunhui Yin ◽  
Yahui He ◽  
...  
Keyword(s):  
Free Energy ◽  
Water Molecule ◽  
Carbonyl Group ◽  
Energy Barrier ◽  
Density Functional ◽  
Free Energy Barrier ◽  
Functional Theory ◽  
Metsulfuron Methyl ◽  
Catalytic Role ◽  
Hydrolysis Of

Sulfonylureas are an important group of herbicides widely used for a range of weeds and grasses control particularly in cereals. However, some of them tend to persist for years in environments. Hydrolysis is the primary pathway for their degradation. To understand the hydrolysis behavior of sulfonylurea herbicides, the hydrolysis mechanism of metsulfuron-methyl, a typical sulfonylurea, was investigated using density functional theory (DFT) at the B3LYP/6-31[Formula: see text]G(d,p) level. The hydrolysis of metsulfuron-methyl resembles nucleophilic substitution by a water molecule attacking the carbonyl group from aryl side (pathway a) or from heterocycle side (pathway b). In the direct hydrolysis, the carbonyl group is directly attacked by one water molecule to form benzene sulfonamide or heterocyclic amine; the free energy barrier is about 52–58[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. In the autocatalytic hydrolysis, with the second water molecule acting as a catalyst, the free energy barrier, which is about 43–45[Formula: see text]kcal[Formula: see text]mol[Formula: see text], is remarkably reduced by about 11[Formula: see text]kcal[Formula: see text]mol[Formula: see text]. It is obvious that water molecules play a significant catalytic role during the hydrolysis of sulfonylureas.

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