Chirality Effects in Biomolecular Systems: Calculation of the Relative Free Energies by Molecular Dynamics Simulations

Chirality plays an essential role in chemical and biological sciences. At the molecular level, the effects associated with this phenomenon can be studied by using the well-established technique of molecular dynamics simulations. In this work, we present several approaches suited for the molecular dynamics-based free energy calculation in chiral systems. In particular, we have proposed and tested the following strategies relying on the application of general, enhanced sampling methods: (i) biased sampling in the two-dimensional space, along the coordinates defined by the values of the selected torsional angles; (ii) biased sampling in the one- or two-dimensional space, along the path-based coordinate(s); (iii) rational alteration of the system’s Hamiltonian in order to enable the interconversion between stereoisomers and reweighting the biased distribution of configurations; (iv) using the free energy landscape generated within approaches (i) or (ii) as time-independent bias in order to further improve sampling efficiency and simultaneously account for multiple chiral centers. All approaches have been tested on a set of model compounds (fenoterol, fructofuranose, and bromochlorofluoromethane), demonstrating the good performance but also some differences in the range of their applicabilities.