Searching for Protein Folding Mechanisms: On the Insoluble Contrast Between Thermodynamic and Kinetic Explanatory Approaches

The protein folding problem is one of the foundational problems of biochemistry and it is still considered unsolved. It basically consists of two main questions: what are the factors determining the stability of the protein’s native structure and how does the protein acquire it starting from an unfolded state. Since its first formulation, two main explanatory approaches have dominated the field of protein folding research: a thermodynamic approach focused on energetic features and a kinetic approach focused on the temporal development of protein chains and structural considerations. Although these two approaches are tightly intertwined in biochemical practice and largely agree on which are the parts and activities in which the phenomenon under study should be decomposed to, there nevertheless exist important contrasts that have had repercussions on the development of the field and still engender vigorous debate. We shall analyse the historical development of the field and crucial aspects of current scientific debates. On this basis, we argue that the main sources of disagreement centre on the causal interpretation of thermodynamic and kinetic explanations, on the explanatory relevance assigned to different features of the phenomena under study and on the status of the ontological assumptions concerning the entities under study.