New Insights into the Relation between Structure and Function, or How Forms Generate Functionality in Living Systems

The development of a proteomics program has led in recent years to a significant elucidation of the relationship between structure and function in biomolecules and to an important revision of the prevailing paradigm that (rigid) structure (linearly) determines function. Several studies on the role played by proteins and proteins interactions in biological phenomena have elucidated several misconceptions regarding the nature of the relation between the structure and function of biomolecules.

(i) Since the overall three-dimensional structure of proteins is always much better conserved than their sequence, it is not uncommon for members of a protein family that possess no more than 10-30% sequence identity to have structures that are practically superimposable. Residues that are critical for maintaining the protein-fold and the ones involved in functional activity tend to be highly conserved. However, since proteins during evolution gradually lose some functions and acquire new ones, the residues implicated in the function will not be necessarily retained even when the protein-fold remains the same. Conservation of protein-fold will then not be correlated with retention of function since a link between structure and function would be expected only if attention were restricted to the functional binding site region instead of the whole protein.

  • (ii) Another difficulty in analyzing correlations between structure and function lies in the fact that individual proteins usually have several functions. It has been estimated that proteins are able, on average, to interact with as many as five partners through a variety of binding sites.
  • (iii) A further ambiguity lies in the term “function” itself. This term is used in different ways and a possible correlation with structure will depend on which aspect of function and which level of biological organization is being considered. Biochemists tend to focus on the molecular level and consider mainly activities like binding, catalysis or signaling. In many instances, the only activity that is discussed is binding activity and function is then taken as synonymous with “binding”. However, functions can also be defined at the cellular and organismic level, in which case they acquire a meaning only with respect to the biological system as a whole, for instance by contributing to its health, performance, survival or reproduction.
  • (iv) Protein functions can also be distinguished in terms of the biological roles they play at the organismic level and this has led to a classification into three classes corresponding to energy-, information- and communication-associated proteins. The link between such biological roles and protein structure is less direct than the one between binding activity and structure, since these functions tend to result from the integrated interactions of many individual proteins or macromolecular assemblies.
  • (v) The prevailing paradigm according to which structure determines function is often interpreted to mean that there is a strict causal relation between structure and function. Although a biological activity always depends on an underlying physical structure, the structure in fact does not possess causal efficacy in bringing about a certain activity. Causal relations are dynamic relations between successive events and not between two material objects or between a geometrical static structure and a physico-chemical event. A biological event such as a binding reaction can thus not be caused by something that is not an event, like the structure of one or both interacting partners. It is also impossible to deduce binding activity from the structure of one of the interacting molecules if a particular relationship with a specific partner has not first been identified. This is because a binding site is essentially a relational entity defined by the interacting partner and not merely by structural features that are identifiable independently of the relational nexus with a particular ligand.

The structure of a binding site, as opposed to the structure of a molecule, cannot be described without considering the binding partner. Since the static geometrical structure of a protein is not the only or most important cause of its function, attempts to analyze structure-function relationships should consist in uncovering correlations rather than (linear) causal relations. A conception shift is thus needed in proteomics, for there is not a unique, necessary and sufficient relation between the three-dimensional structure of a protein and its biological activity, but a nexus of dynamic relationships between protein complexes and their interactions and activities. There is definitely a direct and fundamental link between the topological folding of proteins, the tertiary forms which result from these folding and their dynamics in the context of cell’s activity. However, the biological information of proteins does not derive only from structural information, but also from the complex functional networks that connect specific binding sites at the molecular level to the cell’s activity and to the more global organismic level of organization and functioning.

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