Spontaneous drying of non-polar deep-cavity cavitand pockets in aqueous solution

Barnett, J. Wesley; Sullivan, Matthew R.; Long, Joshua A.; Tang, Du; Nguyen, Thong; Ben‐Amotz, Dor; Gibb, Bruce C.; Ashbaugh, Henry S.

doi:10.1038/s41557-020-0458-8

Cited by 58 publications

(89 citation statements)

References 52 publications

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“…For such analysis, we run a plain molecular dynamics (MD) simulation and find that the number of water molecules inside the cavity fluctuates with a bi-modal distribution between wet and dry states (see Fig. 5 (b)), as observed in a similar system [27]. A typical wet configuration is the one in which three water molecules form a linear cluster inside the cavity, in agreement with results on an analogous system [16].…”

Section: Water Behaviour In the Ligand-free Statesupporting

confidence: 79%

“…We choose this system because, despite its relative simplicity, it retains most of the key features of a biologically relevant protein-ligand system. Very recently, a closely related system has been used to investigate how water flows in and out of the system in the absence of a ligand [27]. Furthermore, its symmetry simplifies the analysis and comparison can be made to existing experiments [28] and theoretical calculations [29,30,31].…”

Section: G3 G4mentioning

confidence: 99%

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The role of water in host-guest interaction

Rizzi

Bonati

Ansari

et al. 2020

Preprint

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One of the main applications of atomistic computer simulations is the calculation of ligand binding energies. The accuracy of these calculations depends on the force field quality and on the thoroughness of configuration sampling. Sampling is an obstacle in modern simulations due to the frequent appearance of kinetic bottlenecks in the free energy landscape. Very often this difficulty is circumvented by enhanced sampling techniques. Typically, these techniques depend on the introduction of appropriate collective variables that are meant to capture the system's degrees of freedom. In ligand binding, water has long been known to play a key role, but its complex behaviour has proven difficult to fully capture. In this paper we combine machine learning with physical intuition to build a non-local and highly efficient water-describing collective variable. We use it to study a set of of host-guest systems from the SAMPL5 challenge. We obtain highly accurate binding energies and good agreement with experiments. The role of water during the binding process is then analysed in some detail.

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Section: Water Behaviour In the Ligand-free Statesupporting

confidence: 79%

Section: G3 G4mentioning

confidence: 99%

The role of water in host-guest interaction

Rizzi

Bonati

Ansari

et al. 2020

Preprint

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“…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%

“…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%

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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“…[13][14][15] In collaboration with the Ben-Amotz and Ashbaugh groups, we recently identied the rst direct evidence of the dewetting of a synthetic host in aqueous solution. 16 Wetting of the pocket was found to be dependent on the precise aperture to the cavity. Thus, pockets with the wider aperture were found to be mostly wetted, whereas the ostensibly identical pocket but with a slightly narrower aperture was found to be primarily dry.…”

Section: Introductionmentioning

confidence: 99%