There are two major approaches to hydrolysis of cellulose, acid hydrolysis, and enzymatic hydrolysis. The enzymatic process is poorly understood and must contain the solution to the recalcitrant nature of cellulosic degradation. The enzymes can be modeled, as well as their interactions with cellulose and even the process of enzymatic hydrolysis. The techniques that will probe the processes and mechanisms are numerous and range from reduced models to all-atom QM/MM and thermodynamic integration. Using reduced models, the structural stabilities and solvation free energies can be determined quickly. Normal mode and elastic network models and quasiharmonic analysis can probe the major structural modes of motion of cellulose, cellulases, xylans, lignins, and their mutual complexes. Mutational studies, using thermodynamic integration, can be performed to reveal the effects on structure and on kinetic behaviors, and even on reaction energetics and mechanisms. Umbrella sampling is a key player in understanding the binding affinities of different binding or catalytic domains on cellulose, or the relative binding affinities on different faces of cellulose or even on different locations of the same face. QM/MM is a tool for probing the hydrolysis reaction inside a cellulase catalytic site. This method is at the stage of development that performance is sufficient and the QM approximations are good enough to follow a reaction quantum mechanically while treating the non-reactive portion of the system classically and have reasonable answers for not much higher computational cost than pure classical simulations. It is expected that exceptionally useful information about the release of energy from reaction, and the accompanying structural changes will come from these numerical experiments.

The steered molecular dynamics, targeted MD, and pulling methods are the tools of choice for initial examination of the process of decrystallization of the cellulose fibers into cellodex­trin chains suitable for hydrolysis to mono — and disaccharides. These kinds of numerical experiments can suggest the energy barriers associated with decrystallization, and suggest more detailed studies such as obtaining PMF profiles from umbrella sampling runs, or free energies of decrystallization from Jarzynski pulling experiments. Beyond that, details about how the solvent plays a role in all the aforementioned processes can be carefully quantified and help to select the most likely and deselect unlikely mechanisms.