Abstract

Next-generation molecular force fields deliver accurate descriptions of non-covalent interactions by employing more elaborate functional forms than their predecessors. Much work has been dedicated to improving the description of the electrostatic potential (ESP) generated by these force fields. A common approach to improving the ESP is by augmenting the point charges on each center with higher-order multipole moments. The resulting anisotropy greatly improves the directionality of the non-covalent bonding, with a concomitant increase in computational cost. In this work, we develop an efficient strategy for enumerating multipole interactions, by casting an efficient spherical harmonic based approach within a particle mesh Ewald (PME) framework. Although the derivation involves lengthy algebra, the final expressions are relatively compact, yielding an approach that can efficiently handle both finite and periodic systems without imposing any approximations beyond PME. Forces and torques are readily obtained, making our method well suited to modern molecular dynamics simulations. There is evidence that the α-synucleinopathies Parkinson’s disease (PD) and the Parkinson variant of multiple system atrophy (MSA-P) overlap at multiple levels. Both disorders are characterized by deposition of abnormally phosphorylated fibrillar α-synuclein within the central nervous system suggesting shared pathophysiological mechanisms. Currently, there is no disease-modifying treatment for MSA. In other senses, it has been previously shown that next-generation active vaccination technology with short peptides, AFFITOPEs®, was effective in two transgenic models of synucleinopathies at reducing behavioral deficits, α-syn accumulation and inflammation. We demonstrate here for the first time an efficient emerging template for drug discovery algorithm for multipole energies and derivatives based on spherical harmonics and extensions to particle α-Synuclein aggregation simulated mesh Ewalds on Amyloid β-sheet helix-rich Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr peptide mimic modulators in α-synucleinopathy interfering amyloidogenesis pathways.

Keywords

Aggregation simulated studies;Amyloid β-sheet; helix-richpeptide; mimic modulators;α-Synuclein; aggregation;emerging templated;rug discovery;α-synucleinopathies;interfering amyloidogenesis pathways; Val-Gly-Gly-Ala-Thr-Thr-Thr-Gly-Val-Thr; multipole energies; spherical harmonics; extensions; particle mesh Ewald;