Ab initio protein structure prediction: the necessary presence of external force field as it is delivered by Hsp40 chaperone

Abstract

Background The aqueous environment directs the protein folding process towards the generation of micelle-type structures, which results in the exposure of hydrophilic residues on the surface (polarity) and the concentration of hydrophobic residues in the center (hydrophobic core). Obtaining a structure without a hydrophobic core requires a different type of external force field than those generated by a water. The examples are membrane proteins, where the distribution of hydrophobicity is opposite to that of water-soluble proteins. Apart from these two extreme examples, the process of protein folding can be directed by chaperones, resulting in a structure devoid of a hydrophobic core. Results The current work presents such example: DnaJ Hsp40 in complex with alkaline phosphatase PhoA-U (PDB ID—6PSI)—the client molecule. The availability of WT form of the folding protein—alkaline phosphatase (PDB ID—1EW8) enables a comparative analysis of the structures: at the stage of interaction with the chaperone and the final, folded structure of this biologically active protein. The fuzzy oil drop model in its modified FOD-M version was used in this analysis, taking into account the influence of an external force field, in this case coming from a chaperone. Conclusions The FOD-M model identifies the external force field introduced by chaperon influencing the folding proces. The identified specific external force field can be applied in Ab Initio protein structure prediction as the environmental conditioning the folding proces.

Hydrophobicity-Based Force Field In Enzymes

“…Such an analysis is currently underway. 53,54 Conclusions resulting from the obtained results reveal the need for a new approach to the de novo design of enzymes. It is not enough to build a system of catalytic residues.…”

“…These conditions are changed by factors such as the amphipathic membrane or the specificity of the periplasmic environment . The diversity resulting from the variability of amino acid sequences is complemented not only by the diversity of the environment in the form of an external force field provided by the changed water characteristics (pH, ionic strength) but also by the presence of other molecules affecting the folding processprefoldin, chaperones, or chaperonins. , These molecules act periodically to support the folding process at a specific stage. Obtaining a significant reduction in the energy barrier, which takes place in the case of enzymatic catalysis, results from the specific arrangement of catalytic residues and the surrounding force field.…”

“…The question of how proteins with high RD are folded remains an open question. Such an analysis is currently underway. , …”

External Force Field for Protein Folding in Chaperonins─Potential Application in In Silico Protein Folding

“…This gives rise to the conclusion that the proteins themselves differ so significantly that the common model (common force field) used produces highly variable results. The current analysis focuses on determining the role of the environment that affects protein folding, especially for chaperonin-mediated folding . The starting point is proteins that when folded in an aqueous environment exhibit structuring with a well-defined hydrophobic core with a polar surface (downhill, fast-folding, ultrafast-folding, and antifreeze proteins type II).…”

“…The current analysis focuses on determining the role of the environment that affects protein folding, especially for chaperonin-mediated folding. 38 The starting point is proteins that when folded in an aqueous environment exhibit structuring with a well-defined hydrophobic core with a polar surface (downhill, fast-folding, ultrafast-folding, and antifreeze proteins type II 18 ). These groups of proteins are examples with structures expressed by low parameter values based on the FOD model: RD and K .…”