Emergence of non-monotonic deep cavity cavitand assembly with increasing portal methylation

Saltzman, Alexander; Tang, Du; Gibb, Bruce C.; Ashbaugh, Henry S.

doi:10.1039/c9me00076c

Cited by 5 publications

(8 citation statements)

References 31 publications

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“…Further simulations were applied to investigate the role of partial endo -methylation of host portal rims in regulating cavitand assembly. 57 Specifically, the assembly of mono-, di-, and tri- endo -methylated cavitands with alkanes was simulated to systematically bridge between hosts 2 and 4 by considering partial constriction of the passage between hosts in a dimeric capsule. The methyl groups were found to moderate the assembly equilibrium between dimeric and monomeric complexes, with monomeric 1:1 complexes with C 7 and C 8 systematically growing in stability as the extent of host methylation increases.…”

Section: Guest-mediated Host Dimerizationmentioning

confidence: 99%

Cavitand Complexes in Aqueous Solution: Collaborative Experimental and Computational Studies of the Wetting, Assembly, and Function of Nanoscopic Bowls in Water

2021

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Water is the dominant liquid on Earth. Despite this, the main focus of supramolecular chemistry research has been on binding and assembly events in organic solvents. This arose because it is more straightforward to synthesize organic-media-soluble hosts and because of the relative simplicity of organic solvents compared to water. Nature, however, relies on water as a solvent, and spurred by this fact, supramolecular chemists have recently been making forays into the aqueous domain to understand water-mediated non-covalent interactions. These studies can benefit from the substantial understanding of the hydrophobic effect and electrostatic interactions developed by physical chemists. Nearly 20 years ago, the Gibb group first synthesized a class of water-soluble host molecules, the deep-cavity cavitands, that possess non-polar pockets that readily bind non-polar moieties in aqueous solution and are capable of assembling into a wide range of complexes with distinct stoichiometries. As such, these amphipathic host species are ideal platforms for studying the role of negatively curved features on guest complexation and the structural requirements for guided assembly processes driven by the hydrophobic effect. Here we review the collaborative experimental and computational investigations between Gibb and Ashbaugh over the past 10 years exploring questions including the following: How does water wet/solvate the non-polar surfaces of non-polar pockets? How does this wetting control the binding of non-polar guests? How does wetting affect the binding of anionic species? How does the nature and size of a guest size impact the assembly of cavitand hosts into multimeric capsular complexes? What are the conformational motifs of guests packed within the confines of capsular complexes? How might the electrostatic environment engendered by hosts impact the properties and reactivity of internalized guests?

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Section: Guest-mediated Host Dimerizationmentioning

confidence: 99%

Cavitand Complexes in Aqueous Solution: Collaborative Experimental and Computational Studies of the Wetting, Assembly, and Function of Nanoscopic Bowls in Water

2021

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“…The reverse can also happen, with multiple ligands binding to a single protein, etc. The same holds true for some host-guest systems, with these systems exhibiting binding that is not 1:1 [58,59], complicating both experimental measurement of binding and computational prediction thereof. In SAMPL7, we worked with experimental collaborators to deliberately ensure the challenge focuses on systems exhibiting 1:1 binding.…”

Section: We Avoid Multimeric Systems Which Introduce Additional Complmentioning

confidence: 99%

“…In SAMPL7, we worked with experimental collaborators to deliberately ensure the challenge focuses on systems exhibiting 1:1 binding. However, the formation of hostguest multimeric complexes can even depend on the guest identity [59].…”

Section: We Avoid Multimeric Systems Which Introduce Additional Complmentioning

confidence: 99%

SAMPL7 Host–Guest Challenge Overview: assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

Amezcua

Khoury

Mobley

2021

J Comput Aided Mol Des

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“…The reverse can also happen, with multiple ligands binding to a single protein, etc. The same holds true for some host-guest systems, with these systems exhibiting binding that is not 1:1 [54,55], complicating both experimental measurement of binding and computational prediction thereof. Here, we worked with experimental collaborators to deliberately ensure the challenge focuses on systems exhibiting 1:1 binding.…”

Section: Here We Avoid Multimeric Systems Which Introduce Additionalmentioning

confidence: 99%

“…Here, we worked with experimental collaborators to deliberately ensure the challenge focuses on systems exhibiting 1:1 binding. However, the formation of host-guest multimeric complexes can even depend on the guest identity [55].…”

Section: Here We Avoid Multimeric Systems Which Introduce Additionalmentioning

confidence: 99%

SAMPL7 Host-Guest Challenge Overview: Assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

Amezcua¹,

Khoury²,

Mobley

2020

Preprint

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The SAMPL challenges focus on testing and driving progress of computational methods to help guide pharmaceutical drug discovery. However, assessment of methods for predicting binding affinities is often hampered by computational challenges such as conformational sampling, protonation state uncertainties, variation in test sets selected, and even lack of high quality experimental data. SAMPL blind challenges have thus frequently included a component focusing on host-guest binding, which removes some of these challenges while still focusing on molecular recognition. Here, we report on the results of the SAMPL7 blind prediction challenge for host-guest affinity prediction. In this study, we focused on three different host-guest categories -- a familiar deep cavity cavitand series which has been featured in several prior challenges (where we examine binding of a series of guests to two hosts), a new series of cyclodextrin derivatives which are monofunctionalized around the rim to add amino acid-like functionality (where we examine binding of a two guests to a series of hosts), and binding of a series of guests to a new acyclic TrimerTrip host which is related to previous cucurbituril hosts. Many predictions used methods based on molecular simulations, and overall success was mixed, though several methods stood out. As in SAMPL6, we find that one strategy for achieving reasonable accuracy here was to make empirical corrections to binding predictions based on previous data for host categories which have been studied well before, though this can be of limited value when new systems are included. Additionally, we found that methods using the AMOEBA polarizable force field had considerable success for the two host categories in which they participated. The new TrimerTrip system was also found to introduce some sampling problems, because multiple conformations may be relevant to binding and interconvert only slowly. Overall, results in this challenge tentatively suggest that further investigation of polarizable force fields for these challenges may be warranted.

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Emergence of non-monotonic deep cavity cavitand assembly with increasing portal methylation

Abstract: Using molecular simulations, we examine the emergence of non-monotonic deep-cavity cavitand assembly patterns into monomeric and dimeric complexes with alkanes of increasing length.

Cited by 5 publications

References 31 publications

Cavitand Complexes in Aqueous Solution: Collaborative Experimental and Computational Studies of the Wetting, Assembly, and Function of Nanoscopic Bowls in Water

Cavitand Complexes in Aqueous Solution: Collaborative Experimental and Computational Studies of the Wetting, Assembly, and Function of Nanoscopic Bowls in Water

SAMPL7 Host–Guest Challenge Overview: assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

SAMPL7 Host-Guest Challenge Overview: Assessing the reliability of polarizable and non-polarizable methods for binding free energy calculations

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