Proteins: Sequence to Structure and Function – Current Status

Abstract

In an era that has been dominated by Structural Biology for the last 30-40 years, a dramatic change of focus towards sequence analysis has spurred the advent of the genome projects and the resultant diverging sequence/structure deficit. The central challenge of Computational Structural Biology is therefore to rationalize the mass of sequence information into biochemical and biophysical knowledge and to decipher the structural, functional and evolutionary clues encoded in the language of biological sequences. In investigating the meaning of sequences, two distinct analytical themes have emerged: in the first approach, pattern recognition techniques are used to detect similarity between sequences and hence to infer related structures and functions; in the second ab initio prediction methods are used to deduce 3D structure, and ultimately to infer function, directly from the linear sequence. In this article, we attempt to provide a critical assessment of what one may and may not expect from the biological sequences and to identify major issues yet to be resolved. The presentation is organized under several subtitles like protein sequences, pattern recognition techniques, protein tertiary structure prediction, membrane protein bioinformatics, human proteome, protein-protein interactions, metabolic networks, potential drug targets based on simple sequence properties, disordered proteins, the sequence-structure relationship and chemical logic of protein sequences.

The Amino Acid-Polyamine-Organocation Superfamily

“…It is frequently claimed and generally accepted that sequence divergence occurs more rapidly than 3D fold changes, and that consequently, primary sequence analyses are less sensitive than X-ray crystallographic data for the purpose of defining common protein origin for highly divergent members of a protein superfamily [Abramson and Wright, 2009;Sael et al, 2012;Shenoy and Jayaram, 2010]. While we agree that both methods can provide strong evidence for homology, we are not convinced that this generally accepted notion is correct.…”

Homology modelling and molecular dynamics simulations of a protein serine/threonine phosphatase stp1 inStaphylococcus aureusN315: a potential drug target

“…The protein sequences were used to detect similarity or identity to infer related structural and functional information. [36] The question about the stability and the validity of the predicted structure always remains. Several structure validation tools and methods, based upon different criteria are available.…”

Optimization Bias in Energy-Based Structure Prediction

“…33 and 34). For whole-protein, ab initio structure prediction, 35 the limitations are thought to be due mainly to the size of the conformational spaces of the target macromolecular systems, 6,36 for which locating the global minimum-energy structures requires extensive search. By contrast, the current study has examined the possibility of errors in energy-based predictions due to biases introduced by differences in the extent of local sampling around conformers being compared in a search.…”