Could Quantum Mechanical Properties Be Reflected on Classical Molecular Dynamics? The Case of Halogenated Organic Compounds of Biological Interest

Essential to understanding life, the biomolecular phenomena have been an important subject in science, therefore a necessary path to be covered to make progress in human knowledge. To fully comprehend these processes, the non-covalent interactions are the key. In this review, we discuss how specific protein-ligand interactions can be efficiently described by low computational cost methods, such as Molecular Mechanics (MM). We have taken as example the case of the halogen bonds (XB). Albeit generally weaker than the hydrogen bonds (HB), the XBs play a key role to drug design, enhancing the affinity and selectivity toward the biological target. Along with the attraction between two electronegative atoms in XBs explained by the σ-hole model, important orbital interactions, as well as relief of Pauli repulsion take place. Nonetheless, such electronic effects can be only well-described by accurate quantum chemical methods that have strong limitations dealing with supramolecular systems due to their high computational cost. To go beyond the poor description of XBs by MM methods, reparametrizing the force-fields equations can be a way to keep the balance between accuracy and computational cost. Thus, we have shown the steps to be considered when parametrizing force-fields to achieve reliable results of complex non-covalent interactions at MM level for In Silico drug design methods.