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.