Quantum chemical descriptors as a modeling framework for large biological structures

In this chapter, we performed a historical recollection of the efforts of applying CDFT reactivity descriptors for large biological structures. We follow their time evolution until the current days, analyzing the reasons why this field of application is still incipient compared to the others used for studying chemical systems. We found that one of the most relevant issues has been associated with the particular characteristics of large biomolecules because of their electronic structure that shows emergent properties tied up to their copolymeric nature, resulting in a high energy degeneracy in the frontier molecular orbitals, for instance. Another identified problem is the lack of software with a good variety of implemented quantum chemical descriptors that can handle large output files from quantum chemical calculations of electronic structures of molecular systems with many atoms. For these reasons, the applications of electron density descriptors for systems relevant to biological processes were mainly performed on fragments of enzymes, employing the same protocols used for small organic systems. Other research groups have tried to estimate the whole structure in the calculations, being able to do so using only linear scaling electronic structure methods and semiempirical Hamiltonians but using the finite differences method, which requires higher computational effort. Recently, strategies of combinations of frontier molecular orbitals to overcome the degeneracy problem and their implementations in a new software, PRIMoRDiA, have made available approximately thirty descriptors for large biological structures, with tools for automatic visualization and data analysis. The software applications include (i) theoretical characterization of enzymatic reaction paths, (ii) ligand–protein binding processes, and (iii) conformational analysis of virus proteases. We expect that with these new implementations, the wealth of information that can be retrieved with the employment of quantum chemical descriptors could be used to unravel the chemistry behind such complex biological machinery.