Why is protein structure prediction so difficult?
Two factors that make protein structure prediction challenging are the nature of the energy functions, and the vast search space. The environment of a protein is populated with many other atoms and molecules. If the program were simulating a process that happened in vacuo or even in a non-polar solvent (instead of the aqueous environment of the cytoplasm) it would be much easier. The presence of polar and polarizable solvent molecules make accurate calculation of electrostatic forces extremely difficult. In addition, the main “force” in protein folding is the hydrophobic effect. This arises from the interactions between atoms within the protein, their interactions with the solvent atoms and the interactions between the solvent atoms. In simulations such as Protinfo, Human Proteome Folding, and Rosetta@Home, the effect of these solvent dependent interactions is approximated in the statistical energies. The development of better solvent models and simulations is another active area of re
