Perspective on the Role of Quantum Mechanical Calculations on Cellular Molecular Interactions

Most computational studies of biologically relevant systems have used Molecular Mechanics (MM). While MM is generally reliable for many applications, chemical reactions and bond formations/breakage are not describable in MM. In contrast, Quantum Mechanics (QM) is an approach that utilizes wavefunctions and/or electron density functions for property and structural analyses and hence does not suffer from such limitations. QM methods can be classified into two main frameworks, ab initio and semi-empirical. Semi-empirical methods utilize experimental or ab initio results to make additional approximations, thereby using a combination of some ab initio calculations and fitted experimental data. Despite the accuracy and general applicability of QM, the major disadvantages are limitations due to the system size. Not surprisingly, hybrid methods that partition the problem at hand into subsystems have been developed. Some of these methods mix QM with MM, and others are strictly QM, but limit the range of interactions. As a result, there exists a plethora of methods, some with fanatical followers, with the result that researchers are often faced with bewildering choices.

This review, perhaps more accurately described as a mini-review or perspective, examines recent calculations on biologically relevant (including biomimetic molecules) in which QM is necessary, to a greater or lesser degree, to obtain results that are consistent with the experiment. The review is not an exposition on the theoretical foundations of different methods, but rather a practical guide for the researcher with an interest in using computational methods to produce biologically, or at least biochemically, useful results. Because of our own specific interests, the Arg-Gly-Asp sequence, or so-called RGD, figures prominently in the work, in terms of size, including oligomers of RGD, and strengths of interactions. A key feature of RGD is its role in the binding of cells to the Extra Cellular Matrix (ECM) depending on the cell type and receptor protein on the cell itself. The ECM is comprised of spectra of biological compounds such as proteoglycans and fibrous proteins; RGD is located and found as a motif on these fibrous proteins. The cell bindings to the ECM are done via integrin-RGD binding. Because metal interactions and hydrogen bonding significantly affect integrin-RGD binding, theoretical methodology beyond MM is needed. IntegrinRGD binding affects the adhesion and movement of cells along the ECM. Hence, these interactions are highly relevant to understanding the spread of cancer in an organism.

Keywords: Molecular mechanics (MM), Quantum mechanics (QM), Neurooncolgy, Glycobiology, Extra cellular matrix (ECM).