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

Lucas De Azevedo Santos,Ingrid G Prandi,Teodorico C Ramalho

doi:10.3389/fchem.2019.00848

Abstract

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.

Highlights

Biological systems are huge, they change in time and they are very sensitive to in vivo conditions like temperature and environment (Ramalho et al, 2009; Freitas et al, 2014; Nair and Miners, 2014; Jurinovich et al, 2015)
The classical Molecular Dynamics (MD) is a computational method based on Molecular Mechanics (MM) physics and its first simulation was performed by Alder and Wainright (Alder and Wainwright, 1959) in the late ‘50s
The US Food and Drug Administration (FDA)1 approved more than 230 New Molecular Entity (NME) drugs

Summary

Introduction

Biological systems are huge, they change in time and they are very sensitive to in vivo conditions like temperature and environment (Ramalho et al, 2009; Freitas et al, 2014; Nair and Miners, 2014; Jurinovich et al, 2015). Due to the wide use of classical MD for protein modeling, here we may highlight two of the most used sets of parameters for biomodelling: AMBER (Assisted Model Building with Energy Refinement) (Case et al, 2014), created by Peter Kollman and his group at the University of California, and CHARMM (Chemistry at Harvard using Molecular Mechanics) (Vanommeslaeghe et al, 2010), initially developed by Martin Karplus and coworkers at Harvard University. These data show the importance of a specific parameterization for new drugs since most general FFs are not able to describe with high accuracy those bonds for molecular dynamics simulations (Santos et al, 2014, 2017).

Results

Conclusion