Practical Protein Chemistry - A. Darbre 1989

Prediction of Peptide and Protein Conformation
Limitations of Traditional Methods

The traditional approach outlined above contains numerous ambiguities, some of which are discussed in this section. Robson et al. [67] highlighted the most critical issues that need to be addressed in the coming years.

1) Better potential Functions must be developed, featuring more rigorous parameters and satisfying a broader range of tests.

2) It is necessary to transition to flexible geometry with variable Bond Lengths and, most importantly, variable valence angles.

3) Since biopeptides function in Water, whereas most experiments utilize A wide variety of other Solvents, Methods must be devised to account for Environmental Effects.

4) Existing methods predict Conformations with the lowest potential energy E(X), whereas experimentally observed conformations correspond to the lowest Free energy F(X). Consequently, predictive methods must calculate free energy directly, which necessitates incorporating the Entropy contribution.

5) The methods examined rely primarily on searching for the lowest-energy conformation by evaluating A large number of variants—a task that is difficult to execute for complex molecules such as Proteins. Indeed, even automated (computer) Minimization aimed at locating the global minimum of an E(X)-type function is largely inadequate for this purpose, because the corresponding potential energy surface features numerous local minima where the search tends to stall. Thus, the multiple-minima problem must be overcome for complex molecules.

Finally, The Study of non-peptide molecules forces us to expand the list of challenges that require resolution. Typically, standard potential functions describe interactions between atomic centers coinciding with nuclear positions. However, atoms contain certain electrons, such as those in lone pairs, characterized by electron density localized at a distance from The Nucleus. As a result, the shape of certain atom types is far from spherical. This lies at The Heart of the problem, which is equally significant when studying peptide molecules. To overcome this difficulty, the orbital force field method proposed by Platt and Robson [51] can be employed.