Behavior of Water near Multimodal Chromatography Ligands and Its Consequences for Modulating Protein-Ligand Interactions

Camille L. Bilodeau, Edmond Y. Lau, David J. Roush, Mark A. Snyder, Steven M. Cramer

Research output: Contribution to journalArticlepeer-review

Abstract

Multimodal chromatography is a powerful approach for purifying proteins that uses ligands containing multiple modes of interaction. Recent studies have shown that selectivity in multimodal chromatographic separations is a function of the ligand structure and geometry. Here, we performed molecular dynamics simulations to explore how the ligand structure and geometry affect ligand-water interactions and how these differences in solution affect the nature of protein-ligand interactions. Our investigation focused on three chromatography ligands: Capto MMC, Nuvia cPrime, and Prototype 4, a structural variant of Nuvia cPrime. First, the solvation characteristics of each ligand were quantified via three metrics: average water density, fluctuations, and residence time. We then explored how solvation was perturbed when the ligand was bound to the protein surface and found that the probability of the phenyl ring dewetting followed the order: Capto MMC > Prototype 4 > Nuvia cPrime. To explore how these differences in dewetting affect protein-ligand interactions, we calculated the probability of each ligand binding to different types of residues on the protein surface and found that the probability of binding to a hydrophobic residue followed the same order as the dewetting behavior. This study illustrates the role that wetting and dewetting play in modulating protein-ligand interactions.

Original languageEnglish (US)
Pages (from-to)6112-6120
Number of pages9
JournalThe journal of physical chemistry. B
Volume125
Issue number23
DOIs
StatePublished - Jun 17 2021
Externally publishedYes

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Surfaces, Coatings and Films
  • Materials Chemistry

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