Abstract
The detailed understanding of the binding of small molecules to proteins is the key for the development of novel drugs or to increase the acceptance of substrates by enzymes. Nowadays, computer-aided design of protein–ligand binding is an important tool to accomplish this task. Current approaches typically rely on high-throughput docking essays or computationally expensive atomistic molecular dynamics simulations. Here, we present an approach to use the recently re-parametrized coarse-grained Martini model to perform unbiased millisecond sampling of protein–ligand interactions of small drug-like molecules. Remarkably, we achieve high accuracy without the need of any a priori knowledge of binding pockets or pathways. Our approach is applied to a range of systems from the well-characterized T4 lysozyme over members of the GPCR family and nuclear receptors to a variety of enzymes. The presented results open the way to high-throughput screening of ligand libraries or protein mutations using the coarse-grained Martini model.
Highlights
The detailed understanding of the binding of small molecules to proteins is the key for the development of novel drugs or to increase the acceptance of substrates by enzymes
We demonstrate the versatility of our approach by simulating ligand binding to different enzymes, namely binding of a substrate to a complex catalytic site of an aminotransferase, which is an important representative of biocatalytic applications and binding of drugs to two members of the kinase family, proto-oncogene tyrosineprotein kinase (c-Src) and the AP2-associated protein kinase 1 (AAK1) involved in virus endocytosis and a potential target for COVID-19 treatment[34]
Our results demonstrate the ability of the reparametrized Martini CG model to reproduce experimental binding modes for a variety of receptors, even in challenging cases as G protein-coupled receptors (GPCRs) where ligand binding occurs in environments of different polarity and the nuclear receptor farnesoid X receptor (FXR) where moderate conformational rearrangement of the binding pocket is induced by ligand binding
Summary
The detailed understanding of the binding of small molecules to proteins is the key for the development of novel drugs or to increase the acceptance of substrates by enzymes. We present an approach to use the recently re-parametrized coarse-grained Martini model to perform unbiased millisecond sampling of protein–ligand interactions of small drug-like molecules. In the case of protein engineering studies, only local mutations around the binding/catalytic site can benefit of docking-based methods To alleviate these shortcomings, molecular dynamics (MD) simulation has become a popular tool in the field of drug design and discovery[9,10]. We demonstrate the versatility of our approach by simulating ligand binding to different enzymes, namely binding of a substrate to a complex catalytic site of an aminotransferase, which is an important representative of biocatalytic applications and binding of drugs to two members of the kinase family, proto-oncogene tyrosineprotein kinase (c-Src) and the AP2-associated protein kinase 1 (AAK1) involved in virus endocytosis and a potential target for COVID-19 treatment[34]
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