Macromolecular simulations, difficulty

The simulation of macromolecular systems involves, in principle, the same difficulties as that of compounds of low-molecular mass, but the polymeric nature of the molecules tends to aggravate the computational problems faced by investigators of small molecules. 

The extensive properties of the overall system that is not in equilibrium, such as volume or energy, are simply the sums of the (almost) equilibrium properties of the subsystems. This simple division of a sample into its subsystems is the type of treatment needed for the description of irreversible processes, as are discussed in Sect. 2.4. Furthermore, there is a natural limit to the subdivision of a system. It is reached when the subsystems are so small that the inhomogeneity caused by the molecular structure becomes of concern. Naturally, for such small subsystems any macroscopic description breaks down, and one must turn to a microscopic description as is used, for example, in the molecular dynamics simulations. For macromolecules, particularly of the flexible class, one frequently finds that a single macromolecule may be part of more than one subsystem. Partially crystalhzed, linear macromolecules often traverse several crystals and surrounding liquid regions, causing difficulties in the description of the macromolecular properties, as is discussed in Sect. 2.5 when nanophases are described. The phases become interdependent in this case, and care must be taken so that a thermodynamic description based on separate subsystems is still valid. 

I focus here on a condensed-phase simulation problem involving the interactions of macromolecular stmctures, small molecules, and solvent. Periodic solid-state systems have their own special set of difficulties and simplifications, which 1 do not discuss. The problems of protein structure prediction, protein-ligand binding, and enzymatic catalysis, which are discussed in the next section, fall into this category. 

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