On the dynamical incompleteness of the Protein Data Bank

Abstract

Major scientific challenges that are beyond the capability of individuals need to be addressed by multi-disciplinary and multi-institutional consortia. Examples of these endeavours include the Human Genome Project, and more recently, the Structural Genomics (SG) initiative. The SG initiative pursues the expansion of structural coverage to include at least one structural representative for each protein family to derive the remaining structures using homology modelling. However, biological function is inherently connected with protein dynamics that can be studied by knowing different structures of the same protein. This ensemble of structures provides snapshots of protein conformational diversity under native conditions. Thus, sequence redundancy in the Protein Data Bank (PDB) (i.e. crystallization of the same protein under different conditions) is therefore an essential input contributing to experimentally based studies of protein dynamics and providing insights into protein function. In this work, we show that sequence redundancy, a key concept for exploring protein dynamics, is highly biased and fundamentally incomplete in the PDB. Additionally, our results show that dynamical behaviour of proteins cannot be inferred using homologous proteins. Minor to moderate changes in sequence can produce great differences in dynamical behaviour. Nonetheless, the structural and dynamical incompleteness of the PDB is apparently unrelated concepts in SG. While the first could be reversed by promoting the extension of the structural coverage, we would like to emphasize that further focused efforts will be needed to amend the incompleteness of the PDB in terms of dynamical information content, essential to fully understand protein function.

“Protein” no longer means what it used to

“…Protein movements were classified using different criteria (for example ( Qi et al., 2005 ; Amemiya et al., 2012 ) and following those criteria it was found that the dynamical behaviour is mostly not conserved during evolution ( Marino-Buslje et al., 2019 ).…”

Ensembles from ordered and disordered proteins reveal similar structural constraints during evolution

“…The existence of conformational ensembles is known since the crystallization of hemoglobin with its two conformational states T and R (deoxy and oxygenated forms) in the early 1960. The growth of Protein Data Bank (PDB) redundancy, refinement and development of techniques such as NMR, SAXS and single molecule spectroscopy over the last years have allowed the experimental characterization of a large number of protein ensembles 2,3 . Structural differences between conformers could result from the relative movements of large domains as rigid bodies 4 , secondary and tertiary element rearrangements 5 , and loop movements 6 .…”

Homology modeling in a dynamical world

“…43 More recently, we found that the dynamical behavior in a given family could change with minor sequence variations making difficult to predict CD by homology. 63 Distributions in Figure 1 show that CD could be as large as the MSD, but it is also evident that most of the proteins in our dataset have modest to low CD, meaning that they could function with very low or absent backbone movements. 43,64,65 Several studies drew attention to the importance of CD in TBM methods, 18,19,27 but the consideration of CD in the study of structure-sequence relationships, as an essential ingredient in TBM methods, was often considered a source of bias or "noise."…”

“…Furthermore, we have recently shown that the distribution of CD in a large dataset of proteins, with experimentally determined CD (approximately 5000 proteins), results in three main groups of proteins with different structure‐function relationships . More recently, we found that the dynamical behavior in a given family could change with minor sequence variations making difficult to predict CD by homology …”