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Z-matrix template-based substitution approach for enumeration of 3D molecular structures.

ABSTRACT: The exhaustive enumeration of 3D chemical structures based on Z-matrix templates has recently been used in the quantum chemical investigation of constitutional isomers, diastereomers and rotamers. This simple yet powerful initial structure generation approach can apply beyond the investigation of compounds of identical formula by quantum chemical methods. This paper provides a comprehensive description of the overall concept followed by a practical tutorial to the approach.•The four steps required for Z-matrix template-based substitution are template construction, generation of tuples for substitution sites, removal of duplicate tuples and substitution on the template.•The generated tuples can be used to create chemical identifiers to query compound properties from chemical databases.•All of these steps are demonstrated in this paper by common model compounds and are very straightforward for an undergraduate audience to reproduce. A comparison of the approach in this paper and other options is also discussed.

SUBMITTER: Lorpaiboon W

PROVIDER: S-EPMC8374508 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Z-matrix template-based substitution approach for enumeration of 3D molecular structures.

Lorpaiboon Wanutcha W Limpanuparb Taweetham T

MethodsX 20210617

The exhaustive enumeration of 3D chemical structures based on Z-matrix templates has recently been used in the quantum chemical investigation of constitutional isomers, diastereomers and rotamers. This simple yet powerful initial structure generation approach can apply beyond the investigation of compounds of identical formula by quantum chemical methods. This paper provides a comprehensive description of the overall concept followed by a practical tutorial to the approach.•The four steps requir ...[more]

PMID: 34430311

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Project description:Senile plaques are extracellular deposits found in patients with Alzheimer's Disease (AD) and are mainly formed by insoluble fibrils of β-amyloid (Aβ) peptides. The mechanistic details about how AD develops are not fully understood yet, but metals such as Cu, Zn, or Fe are proposed to have a non-innocent role. Many studies have also linked the non biological metal aluminum with AD, a species whose concentration in the environment and food has been constantly increasing since the industrial revolution. Gaining a molecular picture of how Al(iii) interacts with an Aβ peptide is of fundamental interest to improve understanding of the many variables in the evolution of AD. So far, no consensus has been reached on how this metal interacts with Aβ, partially due to the experimental complexity of detecting and quantifying the resulting Al(iii)-Aβ complexes. Computational chemistry arises as a powerful alternative to investigate how Al(iii) can interact with Aβ peptides, as suitable strategies could shed light on the metal-peptide description at the molecular level. However, the absence of any reliable template that could be used for the modeling of the metallopeptide structure makes computational insight extremely difficult. Here, we present a novel strategy to generate accurate 3D models of the Al(iii)-Aβ complexes, which still circumvents first principles simulations of metal binding to peptides of Aβ. The key to this approach lies in the identification of experimental structures of the isolated peptide that are favourably pre-organized for the binding of a given metal in configurations of the first coordination sphere that were previously identified as the most stable with amino acid models. This approach solves the problem of the absence of clear structural templates for novel metallopeptide constructs. The posterior refinement of the structures via QM/MM and MD calculations allows us to provide, for the first time, physically sound models for Al(iii)-Aβ complexes with a 1 : 1 stoichiometry, where up to three carboxylic groups are involved in the metal binding, with a clear preference towards Glu3, Asp7, and Glu11.

Dataset Information

Z-matrix template-based substitution approach for enumeration of 3D molecular structures.

Publications

Z-matrix template-based substitution approach for enumeration of 3D molecular structures.

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