Comparative analysis of backbone atom cross-correlation matrices and folding dynamics of amyloid fibril and its complexes with novel biosurfactants isolated from Bacillus strain: a binding free energy calculation (mM-PBSA) and MD simulation approach

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Abstract
In the relentless pursuit of unraveling the intricate pathophysiology of Alzheimer's disease (AD), amyloid β (Aβ) proteins emerge as focal points due to their pivotal role in disease progression. The pathological hallmark of AD involves the aberrant aggregation of Aβ peptides into amyloid fibrils, precipitating a cascade of neurodegenerative events culminating in cognitive decline and neuronal loss. This study adopts a computational framework to investigate the potential therapeutic efficacy of novel biosurfactants (BS) in mitigating Aβ fibril formation. Initial analyses encompassing sequence alignment, structural elucidation, and functional characterization reveal distinctive attributes of the Aβ peptide and the identified BS candidates. Quantum chemical calculations, using the ORCA Program (v4.0) employed Density Functional Theory (DFT), specifically the Becke 3-parameter Lee-Yang-Parr (B3LYP) method, to investigate the electronic structure and energetics of novel isolates. Molecular docking through AutoDock Vina (version 1.1.2) employing advanced algorithms elucidates the binding affinities and interaction energies between Aβ fibrils and BS molecules. The observed binding energy of -7.0 kcal/mol for BG2A and -6.6 kcal/mol for BG2B, underscoring the robustness and stability of the formed complexes. The binding mechanism of docked complexes was predicted through molecular dynamics (MD) simulations using GROMACS 2021.3 and Charmm36 force field, capture complex dynamics over 100 nanoseconds. Analysis via RMSD, RMSF, Rg, PCA, and SASA offers insights into Aβ-BS complex stability and dynamics. These promising results highlight the potential of BG2A and BG2B as therapeutic candidates against AD. However, rigorous preclinical and clinical validation is crucial to ascertain their safety, efficacy, and translational relevance.

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