BAR-based Multi-dimensional Nonequilibrium Pulling for Indirect Construction of QM/MM Free Energy Landscapes: Varying the QM Region

30 March 2021, Version 3
This content is a preprint and has not undergone peer review at the time of posting.


The indirect construction of the free energy landscape at Quantum mechanics (QM)/ molecular mechanics (MM) levels provides a feasible alternative to the direct QM/MM free energy simulations. The main idea under the indirect method is constructing a thermodynamic cycle, exploring the configurational space at a computationally efficient but less accurate low-level Hamiltonian, and performing an alchemical correction to obtain the thermodynamics at an accurate but computationally demanding high-level Hamiltonian. In our previous works, we developed a multi-dimensional nonequilibrium free energy simulation framework to obtain QM/MM free energy landscapes indirectly. Specifically, we considered obtaining semi-empirical QM (SQM) results by combining the MM results and the MM-to-SQM correction and obtaining the QM results by combining the SQM results and the SQM-to-QM correction. In this work, we explore the possibility of changing the region for electronic structure calculations in the multi-scale QM/MM treatment, which could also be considered as a change of the level of theory. More generally, the multi-dimensional nonequilibrium Hamiltonian-variation/perturbation framework could be used to obtain transformations between different Hamiltonians of interest, such as changing the QM theory, the size of the QM region, and the basis set simultaneously.


Free Energy Simulation
Steered Molecular Dynamics
Dihedral Flipping
Conformational Change
Nonequilibirum Pulling
Free Energy Perturbation
Bidirectional Pulling
Bidirectional Perturbation
Enhanced Sampling Techniques
Multi-scale Treatment
Alchemical Free Energy Calculation
semi-empirical quantum calculations
ab initio Quantum Calculations
Hamiltonian Variation
QM Region
Basis set
Bennett Acceptance Ratio
Indirect QM/MM Free Energy Simulation
Sample Size
Pulling Speed
Gas-phase Simulations
Backbone Dihedral
Alanine Tripeptide
Configurational Sampling
Statistical Uncertainty
Time Derivative of Uncertainty


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