Protein Structure and Function. Application of Bioinformatics Methods - John Rigden 2014

Fold recognition
“Threading”

What insights can be drawn from the fact that many significantly different sequences share a similar Spatial Structure? A substantial body of evidence indicates that the naturally occurring (native) state of a protein resides in a broad and deep energy well. Protein folding into its characteristic (often, though not always, unique) structure is driven by energetically favorable interactions among Amino Acids within the structure, as well as between the Amino Acids and the surrounding solvent.

If we could understand which spatial and solvent interactions stabilize a given structure, it would become possible to predict sequences compatible with that structure, as well as to design sequences tailored to it. This is the core concept of threading. Given a sequence whose structure needs to be predicted, a researcher aligns, or “threads,” the query sequence against all known structures in database repositories. A score is calculated for each case, providing an indication of how favorable the given structure is for the sequence in question. The structure with the most favorable score is then selected as the prediction. But what are these favorable interactions, and how can their magnitude be computed? Fortunately, thanks to the dedicated efforts of numerous experimentalists worldwide, a database of native protein structures is available—a database of energetically favorable interactions.

Through rigorous statistical Analysis of the distribution of various amino acid types across known protein structures, it is possible to establish clear sequence-structure relationships and leverage them to solve prediction challenges. These empirical, or “knowledge-based,” force fields are widely utilized across all Methods of Cell/13.html">Protein Structure Prediction, and their pivotal role in ab initio modeling means that many details concerning this problem can be found in the corresponding chapter. Nevertheless, A brief Overview will still be useful.