Solution to the protein folding problem

ARIEL FERNANDEZ

Soft and Biological Matter/ Physics at the Biomolecular Interface

Springer International Publishing

Lugar: Berlin; Año: 2016; p. 71 - 103

This chapter unravels a first-principle solution to the protein folding problem. The solution incorporates the dynamic interplay between the formation of packing defects and the interfacial tension created by such defects. Thus, the solution symbiotically combines a structural and epistructural approach to compute the dynamic entanglement between protein chain and solvent. The structural perspective explores the concept of wrapping, its intimate relation to cooperativity and its bearing on the expediency and reproducibility of the folding process. Wrapping refers to the environmental enhancement of intramolecular electrostatic interactions through anexclusion of surrounding water that takes place as the chain folds onto itself. In thisway a many-body picture of the folding process emerges whereby the folding chain interacts with itself and at the same time shapes the microenvironments that stabilize or destabilize the intramolecular interactions. This picture reflects a dynamic competition between chain folding and backbone hydration, where ultimately,backbone hydrogen bonds prevail through cooperative wrapping, upholding the picture that ?folding is a struggle for the survival of backbone hydrogen bonds?.On the other hand, a solvent-centric or epistructural analysis introduces a crucial component to the free energy of structural assemblage: the reversible work required to span the protein-water interface. Failures of cooperativity, i.e. wrapping deficiencies known as dehydrons, generate interfacial tension. Thus folding is steered by a variational principle of minimal interfacial frustration or, translated into structural terms, of minimization in the number of dehydrons. The interfacial contribution to the free energy complements and steers the many-body wrapping dynamics, leading to the semiempirical solution to the protein folding problem presented in this chapter.