# Fractal Aspects of Human S100 Protein Structures
## 4 Discussion
In some cases, calcium binding may induce a conformational shift that exposes hydrophobic regions or binding sites for other ligands leading to an increase in surface complexity, as the protein might expose additional binding sites or undergo conformational changes that create a more rugged surface [50]. These changes are important for protein function because they modulate its ability to interact with target molecules. For the S100 proteins analyzed, calcium binding produces an increase in the surface fractal dimension for S100A16 from 2.312 for the apo-form (PDB ID 2L50) to 2.471 for the calcium-loaded form (PDB ID 2L51). Structural data reveal that, by comparison to most S100 proteins, the conformational rearrangement of S100A16 upon calcium binding is minor and the change in the surface fractal dimension should mainly be due to the increased hydrophobic interactions between the third and fourth helices of S100A16 [51]. There also is an increase in the surface fractal dimension for S100P from 2.177 for apo-form (PDB ID 1 OZO) to 2.225 for the calcium-loaded S100P in complex with RAGE (PDB ID 2 MJW). The binding of ligands and of calcium and/or sodium ions can significantly alter protein conformation and surface properties. Complexations of these proteins with ligands and/or ions modulate their surface properties by altering surface charge, exposing hydrophobic regions, and/or influencing metal ion specificity, all these resulting in conformational changes. These modifications are crucial for the functional versatility of S100 proteins, allowing them to participate in a variety of cellular processes through dynamic interactions with other biomolecules. Changes in surface fractal dimensions are also recorded when comparing native structures with mutant structures. In the case of S100A1, the CYS85 MET mutation leads to a decrease in the surface fractal dimension from 2.404 for the native protein (PDB ID 2L0P) to 2.297 for the mutant (PDB ID 2 LLS). The conformational change produced by the CYS85 MET mutation in S100A1 was found to be similar to that caused by CYS85 thionylation [47]. It was also revealed that post-translational modifications of S100A1 at CYS85 lead to conformational changes that disrupt the apo-state folding by increasing the solvent exposure of the protein target binding domain (the hydrophobic patch). This increases the calcium sensitivity of binding targets and thus modulates the corresponding signaling pathways [52]. This is consistent with the critical role of cysteine residues in the structural and functional properties of the protein, these residues being usually involved in disulfide bond formation, which contributes to protein stability. The substitution of cysteine with the non-polar amino acid methionine can disrupt disulfide bridges, affecting the tertiary or quaternary structure of the protein. Methionine is bulkier than cysteine, and the resulting structural change could alter the conformation of the calcium-binding domains in S100A1, which may impair the protein's ability to bind calcium and, consequently, its biological function. Consequently, the CYS85 MET mutation in S100A1 is likely to impair its structural integrity, calcium-binding capacity, interaction with target proteins, and redox sensitivity. This mutation could potentially contribute to diseases involving muscle dysfunction or altered calcium homeostasis, especially in the heart and skeletal muscles. In the case of the S100A4 protein, the four mutations (CYS3 SER, CYS76 SER, CYS81 SER, and CYS86 SER) result in the stabilization of the solution structure [53], and the surface fractal dimension changes slightly from 2.313 for the native protein (PDB ID 2 LNK) to 2.308 for the mutant (PDB ID 2 MRD). The decrease in the surface fractal dimension from 2.218 in the case of native S100A4 (PDB ID 4 ETO) to 2.173 for the CYS3 SER, CYS81 SER, CYS86 SER, and PHE45 TRP mutants (PDB ID 4 CFR) has also been noticed when using crystal structures.