How Does the Spliceosome Catalyze Intron Lariat Formation? Insights from Quantum Mechanics/Molecular Mechanics Free-Energy Simulations

2019 ◽  
Vol 123 (28) ◽  
pp. 6049-6055 ◽  
Author(s):  
Wenting Huang ◽  
Yan Huang ◽  
Jun Xu ◽  
Jie-Lou Liao
Keyword(s):  
Free Energy ◽  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Energy Simulations

BAR-based multi-dimensional nonequilibrium pulling for indirect construction of QM/MM free energy landscapes: from semi-empirical to ab initio

2019 ◽  
Vol 21 (39) ◽  
pp. 21942-21959 ◽  
Author(s):  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Quantum Mechanics ◽  
Ab Initio ◽  
Molecular Mechanics ◽  
Indirect Method ◽  
Energy Landscapes ◽  
Free Energy Landscapes ◽  
Energy Simulations ◽  
Semi Empirical

The indirect method for the construction of quantum mechanics (QM)/molecular mechanics (MM) free energy landscapes provides a cheaper alternative for free energy simulations at the QM level.

Calculations of Solvation Free Energy through Energy Reweighting from Molecular Mechanics to Quantum Mechanics

2016 ◽  
Vol 12 (2) ◽  
pp. 499-511 ◽  
Author(s):  
Xiangyu Jia ◽  
Meiting Wang ◽  
Yihan Shao ◽  
Gerhard König ◽  
Bernard R. Brooks ◽  
...  
Keyword(s):  
Free Energy ◽  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Solvation Free Energy

Quantum Mechanics/Molecular Mechanics Free Energy Maps and Nonadiabatic Simulations for a Photochemical Reaction in DNA: Cyclobutane Thymine Dimer

2016 ◽  
Vol 7 (21) ◽  
pp. 4391-4397 ◽  
Author(s):  
Jesús I. Mendieta-Moreno ◽  
Daniel G. Trabada ◽  
Jesús Mendieta ◽  
James P. Lewis ◽  
Paulino Gómez-Puertas ◽  
...  
Keyword(s):  
Free Energy ◽  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Photochemical Reaction ◽  
Thymine Dimer ◽  
Energy Maps ◽  
Cyclobutane Thymine Dimer

scholarly journals Seeding the Multi-dimensional Nonequilibrium Pulling for Hamiltonian Variation: Indirect QM/MM Free Energy Simulations

2021 ◽  
Author(s):  
Zhaoxi Sun ◽  
Qiaole He
Keyword(s):  
Free Energy ◽  
Quantum Mechanics ◽  
Computational Cost ◽  
Selection Criterion ◽  
Energy Difference ◽  
Energy Simulation ◽  
Computationally Efficient ◽  
Free Energy Difference ◽  
Energy Simulations ◽  
Semi Empirical

<p>The combination of free energy simulations in the alchemical and configurational spaces provides a feasible route to access the thermodynamic profiles under a computationally demanding target Hamiltonian. Normally, due to the significant differences between the computational cost of ab initio quantum mechanics (QM) calculations and those of semi-empirical quantum mechanics (SQM) and molecular mechanics (MM), this indirect method is often applied to obtain the QM thermodynamics by combining the SQM or MM thermodynamics and the SQM-to-QM or MM-to-QM corrections. In our previous works, a multi-dimensional nonequilibrium pulling framework for Hamiltonian variations has been introduced based on bidirectional pulling and bidirectional reweighting. The method performs nonequilibrium free energy simulations in the configurational space to obtain the thermodynamic profile along the conformational change pathway under a selected computationally efficient Hamiltonian, and uses the nonequilibrium alchemical method to correct or perturb the thermodynamic profile to that under the target Hamiltonian. The BAR-based method is designed to achieve the best generality and transferability and thus leads to modest (~20 fold) speedup. In this work, we explore the possibility of further accelerating the nonequilibrium free energy simulation by employing unidirectional pulling and using the selection criterion to obtain the initial configurations used to initiate nonequilibrium trajectories following the idea of adaptive steered molecular dynamics (ASMD). A single initial condition is used to seed the whole multi-dimensional nonequilibrium free energy simulation and the sampling is performed fully in the nonequilibrium ensemble. The ASMD scheme estimates the free energy difference with the unidirectional exponential average (EXP), but it does not follow exactly the requirements of the EXP estimator. Another consequence of the seeding simulation is the inherently sequential or serial pulling due to the inter-segment dependency, which triggers some problems in the parallelizability of the simulation. Therefore, some tests are required to grasp some insights and guidelines for using this selection-criterion-based ASMD scheme. The ASMD method is tested thoroughly on a dihedral flipping model system and encouraging numerical results are obtained. The selection-criterion-based multi-dimensional ASMD framework follows the same perturbation framework of the BAR-based method, and thus could be used in various Hamiltonian-variation cases.</p>

scholarly journals Seeding the Multi-dimensional Nonequilibrium Pulling for Hamiltonian Variation: Indirect Nonequilibrium Free Energy Simulations at QM levels

2021 ◽  
Author(s):  
Zhaoxi Sun ◽  
Qiaole He
Keyword(s):  
Free Energy ◽  
Quantum Mechanics ◽  
Computational Cost ◽  
Selection Criterion ◽  
Energy Difference ◽  
Energy Simulation ◽  
Computationally Efficient ◽  
Free Energy Difference ◽  
Energy Simulations ◽  
Semi Empirical

The combination of free energy simulations in the alchemical and configurational spaces provides a feasible route to access the thermodynamic profiles under a computationally demanding target Hamiltonian. Normally, due to the significant differences between the computational cost of ab initio quantum mechanics (QM) calculations and those of semi-empirical quantum mechanics (SQM) and molecular mechanics (MM), this indirect method could be used to obtain the QM thermodynamics by combining the SQM or MM results and the SQM-to-QM or MM-to-QM corrections. In our previous works, a multi-dimensional nonequilibrium pulling framework for Hamiltonian variations has been introduced based on bidirectional pulling and bidirectional reweighting. The method performs nonequilibrium free energy simulations in the configurational space to obtain the thermodynamic profile along the conformational change pathway under a selected computationally efficient Hamiltonian, and uses the nonequilibrium alchemical method to correct or perturb the thermodynamic profile to that under the target Hamiltonian. The BAR-based method is designed to achieve the best generality and transferability and thus leads to modest (~20 folds) speedup. In this work, we explore the possibility of further accelerating the nonequilibrium free energy simulation by employing unidirectional pulling and using the selection criterion to obtain the initial configurations used to initiate nonequilibrium trajectories following the idea of adaptive steered molecular dynamics (ASMD). A single initial condition is used to seed the whole multi-dimensional nonequilibrium free energy simulation and the sampling is performed fully in the nonequilibrium ensemble. Introducing very short ps-length equilibrium sampling to grab more initial seeds could also be helpful. The ASMD scheme estimates the free energy difference with the unidirectional exponential average (EXP), but it does not follow exactly the requirements of the EXP estimator. Another deficiency of the seeding simulation is the inherently sequential or serial pulling due to the inter-segment dependency, which triggers some problems in the parallelizability of the simulation. Numerical tests are performed to grasp some insights and guidelines for using this selection-criterion-based ASMD scheme. The presented selection-criterion-based multi-dimensional ASMD scheme follows the same perturbation network of the BAR-based method, and thus could be used in various Hamiltonian-variation cases.

Quantum mechanics/molecular mechanics dual Hamiltonian free energy perturbation

2013 ◽  
Vol 139 (6) ◽  
pp. 064105 ◽  
Author(s):  
Iakov Polyak ◽  
Tobias Benighaus ◽  
Eliot Boulanger ◽  
Walter Thiel
Keyword(s):  
Free Energy ◽  
Quantum Mechanics ◽  
Molecular Mechanics ◽  
Free Energy Perturbation ◽  
Energy Perturbation
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