The world of molecular simulations of large systems, in particular of biological macromolecules is dominated by classical models where atoms are typically represented by charged spheres connected by springs. These are old approaches, with severe limitations, that were developed more than 40 years ago:

• weak physical models without explicit treatment of  electrons. They are incapable of describing important physical phenomena, for example charge transfer, and of describing important systems such as metallo-proteins.
• Models depend on specific parameterization, rendering them very specific.
• No clear improvement path. In fact current additive force fields had very little improvements in the past 30 years.    
• New generation polarizable force fields, such as models based on the Drude polarizable force field or in charge equilibration, are harder to parameterize and cannot describe additional systems.

It is obvious that replacement of current classical methodologies with QM based technologies is long overdue. In a recent prophetic essay, Grimme and Schreiner predict low-cost QM methods will replace classical force fields in the next two decades¹.

Le roi est mort, vive le roi!

FastCompChem developed solutions to two of the major problems that prevent extension of quantum chemical methods to very large systems, in particular computation of electron repulsion integrals² and diagonalization of very large matrices³. These are fundamental pieces that allow immediate extension of existing methodologies, for example Hartree-Fock and Density Functional Theory methods, to very large systems.

FastCompChem’s vision goes beyond the simple extension of current methodologies and aims at developing from the ground up a new semi-empirical method. Semi-empirical methods, in the broadest sense, date back from the 1960’s, with important developments in the 1980’s that are still being improved today (ex. PM7). DFTB is another example of an approximated method that is of great value today. 

FastCompChem’s new algorithm, named Fast-QUANTA, starts where DFTB is short, addressing many of its limitations. It is being designed with several requirements in mind:

• to be fast and capable of studying very large systems (hundreds of thousands of atoms) 
• To be capable of performing molecular dynamics simulations.
• To be able to study heterogeneous systems, for example at the interface of chemistry, biochemistry and materials science.
• To be able to reproduce experimental condensed-phase and high-level ab initio properties.
• To have a clear future improvement path.

Besides developing new Hamiltonians, FastCompChem is introducing new parameterization strategies to the world of quantum chemistry. One of the reasons for the success of classical force field methods are the parameterization strategies. Parameterization of classical force fields, such as CHARMM, follows strict rules to ensure consistency and include reproduction of experimental condensed phase properties. This is, perhaps, the most important factor that makes inherently crude Hamiltonians usable in practice. In particular, use of condensed phase properties ensures a balanced description of the intermolecular interactions. Similarly, FastCompChem will be using the same approach. 

References:
¹ S. Grimme, P.R. Schreiner, Angew. Chem. Int. Ed. 2018, 57:4170 DOI: 10.1002/anie.201709943

² P.E.M. Lopes, Theor. Chem. Acc. 2017, 136:112 DOI: 10.1007/s00214-017-2142-7

³ P.E.M. Lopes, New Born-Oppenheimer molecular dynamics based on the extended Hueckel method: first results and future developments  arXiv:1810.0768