Proximal charge effects on guest binding to a non-polar pocket

Suating, Paolo; Nguyen, Thong; Ernst, Nicholas; Wang, Yang; Jordan, Jacobs H.; Gibb, Corinne L. D.; Ashbaugh, Henry S.; Gibb, Bruce C.

doi:10.1039/c9sc06268h

Cited by 29 publications

(41 citation statements)

References 44 publications

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“…In this section we describe the details of our own reference calculations, give a general overview of methods used by participants' submissions, summarize key experimental details and methodology (the experimental studies will be published elsewhere [59,60,68]), and describe our statistical analysis and evaluation approach.…”

Section: Methodsmentioning

confidence: 99%

“…Shifts in binding enthalpies and free energies of approximately 10 kcal/mol and 2 kcal/mol respectively [50] have been observed and attributed to the competition between guests and anions leading to entropy-enthalpy trade-offs [9,50]. In addition, experimental and computational simulation results show that de-wetting of GDCCs leads to increased guest affinity, because water cannot compete for the pocket [59,72].…”

Section: Gibb Deep Cavity Cavitands (Gdccs) -Octaacid (Oa) and Exo-ocmentioning

confidence: 99%

“…Of the several members in the GDCC host family [59], two have been used in several previous SAMPL challenges thanks to the Gibb group's participation. Those featured in previous SAMPL challenges include OctaAcid (OA) and tetra-endomethyl OctaAcid (TEMOA).…”

Section: Gibb Deep Cavity Cavitands (Gdccs) -Octaacid (Oa) and Exo-ocmentioning

confidence: 99%

“…GDCCs have been used in SAMPL3-7 and there is much experimental data [9,43,59,72] and insight available. This family of hosts bind guests with a hydrophobic moiety that fits the pocket and a hydrophilic group which points out towards the solvent [9].…”

Section: Gibb Deep Cavity Cavitands (Gdccs) -Octaacid (Oa) and Exo-ocmentioning

confidence: 99%

“…Experimental results suggest all binding was inside the CD-derivative cavity so there is no surface binding. Specific experimental details can be found in the SAMPL7 github repository (see https://github.com/samplchallenges/SAMPL7/tree/master/host_guest) and in the relevant experimental papers [58][59][60] respectively. Binding of one guest (g1) to the GDCC exoOA was undetectable by ITC and NMR ( 1).…”

Section: Experimental Measurementsmentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

Section: Gibb Deep Cavity Cavitands (Gdccs) -Octaacid (Oa) and Exo-ocmentioning

confidence: 99%

Section: Gibb Deep Cavity Cavitands (Gdccs) -Octaacid (Oa) and Exo-ocmentioning

confidence: 99%

Section: Gibb Deep Cavity Cavitands (Gdccs) -Octaacid (Oa) and Exo-ocmentioning

confidence: 99%

Section: Experimental Measurementsmentioning

confidence: 99%

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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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Mikromolare Affinität und höher: synthetische Wirt‐Gast‐Komplexe mit hoher Stabilität

et al. 2023

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Das Design von synthetischen Wirt‐Gast‐Komplexen mit hoher Affinität ist von größter Bedeutung, da sie Schlüsselelemente bei der Konstruktion beispielloser supramolekularer Assemblate, funktioneller Materialien, molekularer Sonden, künstlicher Signaltransduktionsereignisse und Schnittstellen mit der biologischen Welt sind. Dieser Aufsatz sammelt neueste Erfolge im Design von 1 : 1‐Wirt‐Gast‐Komplexen mit führender Stabilität, d. h. über 106 M−1. Die Beziehungen zwischen den gemessenen thermodynamischen Konstanten und den Strukturparametern der interagierenden Arten werden analysiert. Die Designmerkmale von hochaffinen Wirten werden im Licht ihrer Bindeeigenschaften diskutiert. Verschiedene Lösungsmittel und unterschiedliche Arten von nichtkovalenten Wechselwirkungen werden für die Stabilisierung der Komplexe berücksichtigt. Schließlich werden einige Hinweise für das Design zukünftiger synthetischer Rezeptoren mit hoher Affinität und Selektivität gegeben.

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Micromolar Affinity and Higher: Synthetic Host–Guest Complexes with High Stabilities

et al. 2023

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The design of high-affinity synthetic host-guest complexes is of paramount importance because they are key elements in constructing unprecedented supramolecular assemblies, functional materials, molecular probes, artificial signal transduction events, and interfaces with the biological world. The present review article collects recent achievements in the design of 1 : 1 host-guest complexes with outstanding stabilities, i.e., exceeding 10 6 M À 1 . The relationships between the measured thermodynamic constants and the structural parameters of the interacting species are analyzed. The design features of high-affinity hosts are discussed in light of their binding properties. Different solvents and different types of noncovalent interactions are considered for the stabilization of the complexes. Finally, some hints are provided for the design of future synthetic receptors displaying high affinity and selectivity.

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Proximal charge effects on guest binding to a non-polar pocket

Abstract: Science still does not have the ability to accurately predict changes in ligand affinity induced by proximal charged groups.

Cited by 29 publications

References 44 publications

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

Mikromolare Affinität und höher: synthetische Wirt‐Gast‐Komplexe mit hoher Stabilität

Micromolar Affinity and Higher: Synthetic Host–Guest Complexes with High Stabilities

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