Computational insights on the role of metal ions as stabilizers for chaperone-amyloid interactions =

The most common type of dementia, Alzheimer's disease is characterized by a steadily declining neurological state. There are two primary categories of neuropathological alterations in this illness. The first category consists of positive lesions, which are identified in the brains of the afflicted individuals by the build-up of neurofibrillary tangles, amyloid plaques, dystrophic neurites, neuropil threads, and other aberrant deposits. The existence of senile plaques, and extracellular deposits of beta-amyloid protein (Aβ), is one of the main reasons for these alterations. The accumulation of Aβ plays a major role in neurotoxicity, which has several detrimental impacts on the health of neurons. Extracellular misfolded Aβ peptide accumulation is thought to start several years before the observable signs and symptoms of Alzheimer's disease. The majority of Alzheimer's disease treatments now available focus on managing symptoms rather than curing the illness or dramatically slowing its course. A class of conserved proteins known as molecular chaperones prevents freshly generated proteins from misfolding, hence facilitating correct protein folding. It has been demonstrated that the extracellular S100 protein family of metalloproteins affects cellular functions like migration, survival, differentiation, and proliferation in both healthy and pathological settings. One prominent member of the S100 family, S100B, binds to Aβ42 and inhibits its aggregation, suggesting that S100B has a chaperone-like role. Understanding the impact of specific ions, especially transition metals, on S100B's structure and, in turn, the interaction itself, presents the primary research challenge in this field because it has been observed that the activity of S100B is related to the ions coordinated by the protein itself. S100B has a high affinity for calcium and zinc, and other metals and evidences suggests that variation in concentration have an influence on the protein's conformation. It is also known that amyloid alters normal calcium homeostasis, causing an overload in calcium concentration. A molecular-level understanding of the effect of different ionic species on the chaperone activity of S100B can be helpful in hypothesizing a potential future use of this protein in treatments for AD. In this context, molecular dynamics represents an elective tool that is commonly used to study such interactions since it allows for a detailed analysis of molecular systems across time. This work has explored how two conditions of normal and high concentration of Calcium influence the S100B amyloid interaction. A Quantum Mechanics/Molecular Mechanics (QM/MM) approach was employed to optimize parameters for the protein ions interaction of the two conditions. The molecular dynamics investigation revealed that the high calcium concentration model exhibited reduced chaperone function compared to the other condition. This difference results in a reduced stability in interaction between the S100Band the amyloid N-terminal region. Nonetheless, our results offers a robust basis for additional investigations of S100B in alternative environment at different ions concentrations, moreover the model could be employed to design and optimize chaperon proteins, with increased activity depending on its environment.