Binding of proteins to copolymers of varying charges and hydrophobicity: a molecular mechanism and computational strategies
File(s)
Accepted version
Author(s)
Xu, Xiao
Zhang, Tong
Angioletti-Uberti, Stefano
Lv, Yongqin
Type
Journal Article
Abstract
Because of their ability to selectively bind to a target protein, copolymer nanoparticles (NPs) containing a selected combination of hydrophobic and charged groups have been frequently reported as potent antibody-like analogues. However, due to the intrinsic disorder of the copolymer NP in terms of its random monomer sequence and the cross-linked copolymer matrix, the copolymer NP is indeed strikingly different from a well-folded protein antibody and the complexation between the copolymer NP and a target protein is likely not due to a lock-key type of interaction but possibly due to a novel and unexplored molecular mechanism. Here, we study a key biomarker protein, vimentin, interacting with a set of random copolymer chains using implicit-water explicit-ion coarse-grained (CG) molecular dynamics (MD) simulations along with biolayer interferometry (BLI) analysis. Due to the charge and hydrophobicity anisotropy on the vimentin dimer (VD) surface, a set of bound copolymers are found inhomogenously adsorbed on the VD, with energetic heterogeneity for different binding sites and cooperative effect in the adsorption. Increasing the charge or hydrophobicity of the copolymer may have different consequences on the adsorption. In this study, we found that with more copolymer charges, the protein coverage increases for copolymers of low hydrophobicity and decreases of high hydrophobicity, which is explained by the distribution and size of various functional patches on the VD in loading those copolymers. Employing a coverage-dependent Langmuir model, we propose a simulation protocol to address the full profile of the copolymer binding free energy through the fit to the simulated binding isotherm. The obtained results correlate well with those from the BLI experiment, indicating the significance of this method for the rational design of the copolymer NP with engineered protein binding affinity.
Date Issued
2022-10-10
Date Acceptance
2022-09-21
Citation
Biomacromolecules, 2022, 23 (10), pp.4118-4129
ISSN
1525-7797
Publisher
American Chemical Society
Start Page
4118
End Page
4129
Journal / Book Title
Biomacromolecules
Volume
23
Issue
10
Copyright Statement
© 2022 American Chemical Society. This document is the Accepted Manuscript version of a Published Work that appeared in final form in [JournalTitle], after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.biomac.2c00521, see ACS Articles on Request https://pubs.acs.org/page/4authors/benefits/index.html#articles-request
Publication Status
Published
Date Publish Online
2022-09-27