Issue 13, 2020

Impact of electronic polarizability on protein-functional group interactions

Abstract

Interactions of proteins with functional groups are key to their biological functions, making it essential that they be accurately modeled. To investigate the impact of the inclusion of explicit treatment of electronic polarizability in force fields on protein-functional group interactions, the additive CHARMM and Drude polarizable force field are compared in the context of the Site-Identification by Ligand Competitive Saturation (SILCS) simulation methodology from which functional group interaction patterns with five proteins for which experimental binding affinities of multiple ligands are available, were obtained. The explicit treatment of polarizability produces significant differences in the functional group interactions in the ligand binding sites including overall enhanced binding of functional groups to the proteins. This is associated with variations of the dipole moments of solutes representative of functional groups in the binding sites relative to aqueous solution with higher dipole moments systematically occurring in the latter, though exceptions occur with positively charged methylammonium. Such variation indicates the complex, heterogeneous nature of the electronic environments of ligand binding sites and emphasizes the inherent limitation of fixed charged, additive force fields for modeling ligand–protein interactions. These effects yield more defined orientation of the functional groups in the binding pockets and a small, but systematic improvement in the ability of the SILCS method to predict the binding orientation and relative affinities of ligands to their target proteins. Overall, these results indicate that the physical model associated with the explicit treatment of polarizability along with the presence of lone pairs in a force field leads to changes in the nature of the interactions of functional groups with proteins versus that occurring with additive force fields, suggesting the utility of polarizable force fields in obtaining a more realistic understanding of protein–ligand interactions.

Graphical abstract: Impact of electronic polarizability on protein-functional group interactions

Supplementary files

Article information

Article type
Paper
Submitted
07 Қаң. 2020
Accepted
11 Нау. 2020
First published
13 Нау. 2020

Phys. Chem. Chem. Phys., 2020,22, 6848-6860

Impact of electronic polarizability on protein-functional group interactions

H. Goel, W. Yu, V. D. Ustach, A. H. Aytenfisu, D. Sun and A. D. MacKerell, Phys. Chem. Chem. Phys., 2020, 22, 6848 DOI: 10.1039/D0CP00088D

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements