Seeding the multi-dimensional nonequilibrium pulling for Hamiltonian variation: indirect nonequilibrium free energy simulations at QM levels

Abstract

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 work, a multi-dimensional nonequilibrium pulling framework for Hamiltonian variations was 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. 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.