Study Suggests Drug Side Effects Inevitable; Basic Physics Enabled Early Biochemistry
A new study of both computer-created and natural proteins suggests that the number of unique pockets – sites where small molecule pharmaceutical compounds can bind to proteins – is surprisingly small, meaning drug side effects may be impossible to avoid. The study also found that the fundamental biochemical processes needed for life could have been enabled by the simple physics of protein folding.
Studying a set of artificial proteins and comparing them to natural proteins, researchers at the Georgia Institute of Technology have concluded that there may be no more than about 500 unique protein pocket configurations that serve as binding sites for small molecule ligands. Therefore, the likelihood that a molecule intended for one protein target will also bind with an unintended target is significant, said Jeffrey Skolnick, a professor in the School of Biology at Georgia Tech. Read more...
"Why not consider a spherical protein? Implications for backbone hydrogen bonding for protein structure and function."
INSIDE COVER: Physical Chemistry Chemical Physics.
Abstract: The intrinsic ability of protein structures to exhibit the geometric features required for molecular function in the absence of evolution is examined in the context of three systems: the reference set of real, single domain protein structures, a library of computationally generated, compact homopolypeptides, artificial structures with protein-like secondary structural elements, and quasi-spherical random proteins packed at the same density as proteins but lacking backbone secondary structure and hydrogen bonding. Without any evolutionary selection, the library of artificial structures has similar backbone hydrogen bonding, global shape, surface to volume ratio and statistically significant structural matches to real protein global structures. Moreover, these artificial structures have native like ligand binding cavities, and a tiny subset has interfacial geometries consistent with native-like protein–protein interactions and DNA binding. In contrast, the quasi-spherical random proteins, being devoid of secondary structure, have a lower surface to volume ratio and lack ligand binding pockets and intermolecular interaction interfaces. Surprisingly, these quasi-spherical random proteins exhibit protein like distributions of virtual bond angles and almost all have a statistically significant structural match to real protein structures. This implies that it is local chain stiffness, even without backbone hydrogen bonding, and compactness that give rise to the likely completeness of the library solved single domain protein structures. These studies also suggest that the packing of secondary structural elements generates the requisite geometry for intermolecular binding. Thus, backbone hydrogen bonding plays an important role not only in protein structure but also in protein function. Such ability to bind biological molecules is an inherent feature of protein structure; if combined with appropriate protein sequences, it could provide the non-zero background probability for low-level function that evolution requires for selection to occur.
New Study Classifies and Analyzes Protein-Protein Interfaces
Interactions between proteins are at the heart of cellular processes, and those interactions depend on the interfaces where the direct physical contact occurs. A new study published this week suggests that there may be roughly a thousand structurally-distinct protein-protein interfaces -- and that their structures depend largely on the simple physics of the proteins.