Do theoretical physicists care about the protein-folding problem?
The prediction of the biologically active native conformation of a protein is one of the fundamental challenges of structural biology. This problem remains yet unsolved mainly due to three factors: the partial knowledge of the effective free energy function that governs the folding process, the enormous size of the conformational space of a protein and, finally, the relatively small differences of energy between conformations, in particular, between the native one and the ones that make up the unfolded state. Herein, we recall the importance of taking into account, in a detailed manner, the many interactions involved in the protein folding problem (such as steric volume exclusion, Ramachandran forces, hydrogen bonds, weakly polar interactions, coulombic energy or hydrophobic attraction) and we propose a strategy to effectively construct a free energy function that, including the effects of the solvent, could be numerically tractable. It must be pointed out that, since the internal free energy function that is mainly described does not include the constraints of the native conformation, it could only help to reach the 'molten globule' state. We also discuss about the limits and the lacks from which suffer the simple models that we, physicists, love so much.