Interactions of Multimodal Ligands with Proteins: Insights into Selectivity Using Molecular Dynamics Simulations

Parimal, Siddharth; Garde, Shekhar; Cramer, Steven M.

doi:10.1021/acs.langmuir.5b00236

Cited by 24 publications

(21 citation statements)

References 44 publications

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“…In a recent paper we have reported that negatively charged multimodal cation exchange ligands—Capto MMC and Nuvia cPrime—interacted with positive and hydrophobic regions on the surfaces of proteins ubiquitin, cytochrome C and α‐chymotrypsinogen A. Further, it was shown that these ligands did not interact with negatively charged protein regions.…”

Section: Resultsmentioning

confidence: 96%

“…All‐atom explicit–solvent MD simulations were performed to understand the binding of arginine and guanidine molecules to protein surfaces. Recent work in our group has focused extensively on the behavior of three model proteins—ubiquitin, cytochrome C, and α‐chymotrypsinogen A—in multimodal ligand systems . Since ubiquitin and cytochrome C exhibited decreased retentions in the presence of guanidine and α‐chymotrypsinogen A exhibited minimal change in retention, these proteins were selected as representatives of this proteins’ set for the first round of analysis using MD simulations.…”

Section: Resultsmentioning

confidence: 99%

“…Protein surface characterization is then performed for a broader set of proteins using faster, coarse‐grained techniques to evaluate the electrostatic and hydrophobic regions on their surfaces. This work builds upon previous work in our lab using a spherical harmonics approach to calculate the density profiles of multimodal cation‐exchange ligands (Capto MMC and Nuvia cPrime) around proteins . Both Capto MMC and Nuvia cPrime ligands have a carboxylate, a benzene and an amide group, with an additional aliphatic group for the Capto MMC ligand, and an extra amine group for the Nuvia cPrime ligand.…”

Section: Introductionmentioning

confidence: 95%

“…This work builds upon previous work in our lab using a spherical harmonics approach to calculate the density profiles of multimodal cation-exchange ligands (Capto MMC and Nuvia cPrime) around proteins. 28,29 Both Capto MMC and Nuvia cPrime ligands have a carboxylate, a benzene and an amide group, with an additional aliphatic group for the Capto MMC ligand, and an extra amine group for the Nuvia cPrime ligand. It was found that these ligands interacted with positive and hydrophobic regions on the proteins.…”

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confidence: 99%

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Effect of guanidine and arginine on protein–ligand interactions in multimodal cation‐exchange chromatography

Parimal

Garde

Cramer

2017

Biotechnology Progress

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The addition of fluid phase modifiers provides significant opportunities for increasing the selectivity of multimodal chromatography. In order to optimize this selectivity, it is important to understand the fundamental interactions between proteins and these modifiers. To this end, molecular dynamics (MD) simulations were first performed to study the interactions of guanidine and arginine with three proteins. The simulation results showed that both guanidine and arginine interacted primarily with the negatively charged regions on the proteins and that these regions could be readily predicted using electrostatic potential maps. Protein surface characterization was then carried out using computationally efficient coarse-grained techniques for a broader set of proteins which exhibited interesting chromatographic retention behavior upon the addition of these modifiers. It was shown that proteins exhibiting an increased retention in the presence of guanidine possessed hydrophobic regions adjacent to negatively charged regions on their surfaces. In contrast, proteins which exhibited a decreased binding in the presence of guanidine did not have hydrophobic regions adjacent to negatively charged patches. These results indicated that the effect of guanidine could be described as a combination of competitive binding, charge neutralization and increased hydrophobic interactions for certain proteins. In contrast, arginine resulted in a significant decrease in protein retention times primarily due to competition for the resin and steric effects, with minimal accompanying increase in hydrophobic interactions. The approach presented in this paper which employs MD simulations to guide the application of coarse-grained approaches is expected to be extremely useful for methods development in downstream bioprocesses. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:435-447, 2017.

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Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 95%

mentioning

confidence: 99%

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Effect of guanidine and arginine on protein–ligand interactions in multimodal cation‐exchange chromatography

Parimal

Garde

Cramer

2017

Biotechnology Progress

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“…Yu et al employed coarse-grained simulations to investigate the preferred binding orientation of lysozyme on a HCIC surface at different ligand densities under a range of salt concentrations (Yu, Liu, & Zhou, 2015). Our lab has been actively involved in studying the preferred binding regions of small proteins in MM CEX systems by employing protein libraries (Chung, Hou, et al, 2010), MD simulations Freed, Garde, & Cramer, 2011;Parimal, Garde, & Cramer, 2015, 2017, Atomic Force Microscopy (AFM) (Srinivasan et al, 2017) and Nuclear Magnetic Resonance (NMR) Holstein, Chung, et al, 2012;Holstein, Parimal, McCallum, & Cramer, 2013;Srinivasan, Parimal, Lopez, McCallum, & Cramer, 2014).…”

Section: Introductionmentioning

confidence: 99%

Identification of Preferred Multimodal Ligand Binding Regions on IgG1 FC using Nuclear Magnetic Resonance and Molecular Dynamics Simulations

Gudhka

Bilodeau

McCallum

et al. 2020

Preprint

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In this study, the binding of multimodal chromatographic ligands to the IgG1 FC domain were studied using nuclear magnetic resonance and molecular dynamics simulations. Nuclear magnetic resonance experiments carried out with chromatographic ligands and a perdeuterated 15N-labeled FC domain indicated that while single mode ion exchange ligands interacted very weakly throughout the FC surface, multimodal ligands interacted with specific clusters of residues with relatively high affinity, forming distinct binding regions on the Fc. The multimodal ligand binding sites on the FC were concentrated in the hinge region and near the interface of the CH2 and CH3 domains. Further, the multimodal binding sites were primarily composed of positively charged, polar and aliphatic residues in these regions, with histidine residues exhibiting some of the strongest binding affinities with the multimodal ligand. Interestingly, comparison of protein surface property data with ligand interaction sites indicated that the patch analysis on FC corroborated molecular level binding information obtained from the nuclear magnetic resonance experiments. Finally, molecular dynamics simulation results were shown to be qualitatively consistent with the nuclear magnetic resonance results and to provide further insights into the binding mechanisms. An important contribution to multimodal ligand-FC binding in these preferred regions was shown to be electrostatic interactions and pi-pi stacking of surface exposed histidines with the ligands. This combined biophysical and simulation approach has provided a deeper molecular level understanding of multimodal ligand-FC interactions and sets the stage for future analyses of even more complex biotherapeutics.

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Identification of preferred multimodal ligand‐binding regions on IgG1 F_C using nuclear magnetic resonance and molecular dynamics simulations

Gudhka

Bilodeau

McCallum

et al. 2020

Biotech & Bioengineering

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In this study, the binding of multimodal chromatographic ligands to the IgG1 FC domain were studied using nuclear magnetic resonance and molecular dynamics simulations. Nuclear magnetic resonance experiments carried out with chromatographic ligands and a perdeuterated 15N‐labeled FC domain indicated that while single‐mode ion exchange ligands interacted very weakly throughout the FC surface, multimodal ligands containing negatively charged and aromatic moieties interacted with specific clusters of residues with relatively high affinity, forming distinct binding regions on the FC. The multimodal ligand‐binding sites on the FC were concentrated in the hinge region and near the interface of the CH2 and CH3 domains. Furthermore, the multimodal binding sites were primarily composed of positively charged, polar, and aliphatic residues in these regions, with histidine residues exhibiting some of the strongest binding affinities with the multimodal ligand. Interestingly, comparison of protein surface property data with ligand interaction sites indicated that the patch analysis on FC corroborated molecular‐level binding information obtained from the nuclear magnetic resonance experiments. Finally, molecular dynamics simulation results were shown to be qualitatively consistent with the nuclear magnetic resonance results and to provide further insights into the binding mechanisms. An important contribution to multimodal ligand‐FC binding in these preferred regions was shown to be electrostatic interactions and π–π stacking of surface‐exposed histidines with the ligands. This combined biophysical and simulation approach has provided a deeper molecular‐level understanding of multimodal ligand–FC interactions and sets the stage for future analyses of even more complex biotherapeutics.

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Interactions of Multimodal Ligands with Proteins: Insights into Selectivity Using Molecular Dynamics Simulations

Cited by 24 publications

References 44 publications

Effect of guanidine and arginine on protein–ligand interactions in multimodal cation‐exchange chromatography

Effect of guanidine and arginine on protein–ligand interactions in multimodal cation‐exchange chromatography

Identification of Preferred Multimodal Ligand Binding Regions on IgG1 FC using Nuclear Magnetic Resonance and Molecular Dynamics Simulations

Identification of preferred multimodal ligand‐binding regions on IgG1 F_C using nuclear magnetic resonance and molecular dynamics simulations

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Interactions of Multimodal Ligands with Proteins: Insights into Selectivity Using Molecular Dynamics Simulations

Cited by 24 publications

References 44 publications

Effect of guanidine and arginine on protein–ligand interactions in multimodal cation‐exchange chromatography

Effect of guanidine and arginine on protein–ligand interactions in multimodal cation‐exchange chromatography

Identification of Preferred Multimodal Ligand Binding Regions on IgG1 FC using Nuclear Magnetic Resonance and Molecular Dynamics Simulations

Identification of preferred multimodal ligand‐binding regions on IgG1 FC using nuclear magnetic resonance and molecular dynamics simulations

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Identification of preferred multimodal ligand‐binding regions on IgG1 F_C using nuclear magnetic resonance and molecular dynamics simulations