How Altered Folding Enables Protein Stability in Aqueous Environments

Knowledge of the spatial structure of a protein is essential for determining its biological activity and critical for the design of drugs using In Silico techniques. Despite the significant advances in protein structure prediction based on a specific amino acid sequence achieved by the AlphaFold technique based on artificial intelligence through the introduction of artificial intelligence (deep learning) methods in 3D structure prediction methodology, the question concerning the mechanism of the folding process remains unanswered. In the current work, achieving an appropriate ordering of the hydrophobicity distribution in the 3D structure was identified as a determining factor for protein structuring. This paper discusses the structuring process as dependent on two factors: external (environment like water or membrane for example) and internal force field (non-bonding interaction in protein body). The objects of the analysis are proteins with a single mutation showing a different secondary structure and an example of the chameleon sequence, where certain segments with an identical sequence adopt different forms of secondary structure. The paper presents a theoretical model with appreciation to Protein Data Bank and ChSeq databases. The analysis used the fuzzy oil drop model in its modified version (FOD-M). The analysis was performed with In Silico techniques using software of open access status. The importance of the environmental contribution was demonstrated by four proteins with targeted single mutations leading to a change in secondary structure from helical to β. It has also been demonstrated in the example of chameleon sequences with segments of 7 amino acids of identical sequence take adopt different forms of secondary structure. The role of environmental conditions in the folding process was demonstrated quantitatively with a mathematical function, the optimization of which should lead to a structure with a defined biological function. The application of the discussed model introduces the possibility of controlling the folding process. The analysis supports the hypothesis of the folding process as the effect of consensus between the internal force field (non-bonding interaction in the protein body) and external force field which directs the process toward the structure appropriate for environment specificity (water/membrane).