Dual-topology/dual-coordinate free-energy simulation using QM/MM force field

2005 ◽  
Vol 123 (4) ◽  
pp. 041102 ◽  
Author(s):  
Hao Hu ◽  
Weitao Yang
Keyword(s):  
Free Energy ◽  
Force Field ◽  
Energy Simulation

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>

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>

Quantum Chemical and Free Energy Simulation Analysis of Retinal Conformational Energetics

1997 ◽  
Vol 37 (6) ◽  
pp. 1018-1024 ◽  
Author(s):  
Jérôme Baudry ◽  
Serge Crouzy ◽  
Benoît Roux ◽  
Jeremy C. Smith
Keyword(s):  
Free Energy ◽  
Quantum Chemical ◽  
Simulation Analysis ◽  
Energy Simulation
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