On the Role of Physics and Evolution in Dictating Protein Structure and Function

Abstract

How many of the structural and functional properties of proteins are inherent? Computer simulations provide a powerful tool to address this question. A series of studies on QS, quasi-spherical, compact polypeptides which lack any secondary structure; ART, artificial, proteins comprised of compact homopolypeptides with protein-like secondary structure; and PDB, native, single domain proteins shows that essentially all native global folds, pockets and protein-protein interfaces are in the ART library. This suggests that many protein properties are inherent and that evolution is involved in fine-tuning. The completeness of the space of ligand binding pockets and protein-protein interfaces suggests that promiscuous interactions are intrinsic to proteins and that the capacity to perform the biochemistry of life at low level does not require evolution. If so, this has profound consequences for the origin of life.

Catalytic and substrate promiscuity: distinct multiple chemistries catalysed by the phosphatase domain of receptor protein tyrosine phosphatase

“…Moreover, it has been argued that even in cases where catalytic promiscuity is seen there needs to be a common substrate substructure that might facilitate the binding and hence, catalysis i.e., an appropriate anchor group or chemophore might lead the substrate to bind to a larger, and often diverse, number of pockets with the right alignment of active site residues (44). In fact, in a previous study from our group, we have demonstrated that the limited number of geometrical pockets that are present in biologically occurring proteins (9) suggests that promiscuity should be the rule rather than exception. Given the small fraction of amino acids that are usually found in the active sites of enzymes and the high probability of their co-occurrence in other pockets (9, 10, 33, 34), lead us to conclude that promiscuous activities ought to be more widespread than was previously assumed.…”

“…In fact, in a previous study from our group, we have demonstrated that the limited number of geometrical pockets that are present in biologically occurring proteins (9) suggests that promiscuity should be the rule rather than exception. Given the small fraction of amino acids that are usually found in the active sites of enzymes and the high probability of their co-occurrence in other pockets (9, 10, 33, 34), lead us to conclude that promiscuous activities ought to be more widespread than was previously assumed.…”

“…It has been recently demonstrated that the library of native pockets is covered by a remarkably small number (~400) of representative pockets (9). With that in mind, one might expect that basal enzymatic activity is an inherent feature of those pockets having an accidental juxtaposition of residues that have been demonstrated to have a role in catalysis (33, 34).…”

“…With that in mind, one might expect that basal enzymatic activity is an inherent feature of those pockets having an accidental juxtaposition of residues that have been demonstrated to have a role in catalysis (33, 34). Indeed, native like enzymatic pockets with catalytic residue types and geometries are reproduced in proteins lacking any selection for enzymatic function (9, 10). With these results in mind, we selected the phosphatase domain of PTPRδ as the protein of interest.…”

“…Further, instances of promiscuity have been extensively reported from members belonging to the haloacid dehalogenase superfamily (1, 6), thioesterases from the hotdog fold superfamily (1) and others (7, 8). Demonstration of the limited number of distinct ligand binding pockets and the emergence of catalytic pockets in proteins without selection for function has further strengthened the understanding that promiscuity and catalysis are inherent features of proteins and that it is very likely (and certainly not surprising) that the tremendous rate accelerations that we see with present day enzymes results from evolutionary selection from a significant random background (9, 10). However, it has been pointed out that most of these promiscuous secondary activities emerge from the same pocket with nature utilizing the same microenvironment optimized to enhance catalytic potential (2).…”