Towards protein folding by global energy optimization.

Different components of the theoretical protein folding problem are evaluated critically. It is argued that: (i) as a rule, small- and medium-sized proteins are in the free energy minimum; (ii) long-living metastable states may either appear occasionally with growing protein size, or be selected by evolution for a specific function; (iii) functions discriminating against incorrect folds would fail if they were used directly in the global optimization, unless they approximate the true free energy accurately; (iv) surface and electrostatic free energies should be treated separately; (v) conformational entropy (of side chains in particular) should be taken into account; (vi) Monte Carlo procedures considering all free energy terms and combining global knowledge-based random moves with local optimization have the largest potential for success.