Abstract
Enveloping distribution sampling (EDS) is an efficient approach to calculate multiple free-energy differences from a single molecular dynamics (MD) simulation. However, the construction of an appropriate reference-state Hamiltonian that samples all states efficiently is not straightforward. We propose a novel approach for the construction of the EDS reference-state Hamiltonian, related to a previously described procedure to smoothen energy landscapes. In contrast to previously suggested EDS approaches, our reference-state Hamiltonian preserves local energy minima of the combined end-states. Moreover, we propose an intuitive, robust and efficient parameter optimization scheme to tune EDS Hamiltonian parameters. We demonstrate the proposed method with established and novel test systems and conclude that our approach allows for the automated calculation of multiple free-energy differences from a single simulation. Accelerated EDS promises to be a robust and user-friendly method to compute free-energy differences based on solid statistical mechanics.
Highlights
In computational drug design, molecular dynamics (MD)simulations are increasingly used to calculate precise binding free energy estimates for novel drug candidates and aid the development thereof.[1]
We demonstrate the proposed method with established and novel test systems and conclude that our approach allows for the automated calculation of multiple free-energy differences from a single simulation
Accelerated Enveloping distribution sampling (EDS) promises to be a robust and user-friendly method to compute free-energy differences based on solid statistical mechanics
Summary
Simulations are increasingly used to calculate precise binding free energy estimates for novel drug candidates and aid the development thereof.[1]. The unmodified EDS Hamiltonian HR(r⃑) can be accelerated by setting Emin and Emax such that the maximum energy barrier between the states, ΔEmax, is reduced to a userdefined parameter ΔEm*ax in HR*(r ⃑). In panel A, the reference state Hamiltonian with a parameter s according to eq 3 is shown Note that both energy minima are shifted on the reaction coordinate and regarding their relative energy levels. Hamiltonian was constructed according to the proposed A-EDS formulation given in eq 4 This reference state Hamiltonian HR*(r ⃑) preserves the energy minima with respect to their position on the reaction coordinate and their relative energy levels and the energy barrier between the minima is reduced to a small, desired value. In panels B and C, A-EDS parameters Emax and Emin, and the target maximum energy barrier height ΔEm*ax are shown with red solid and dashed lines, respectively. Before the free energy parameters are optimized, they are all set to zero or to the values of the relative energy differences between the states in the beginning of the simulation
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