D3R grand challenge 4: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies

parks, conor; Gaieb, Zied; Chiu, Michael; Yang, Huanwang; Shao, Chenghua; Walters, W. Patrick; Jansen, Johanna M.; McGaughey, Georgia B.; Lewis, Richard A.; Bembenek, Scott D.; Ameriks, Michael K.; Mirzadegan, Taraneh; Burley, S.K.; Amaro, Rommie E.; Gilson, Michael K.

doi:10.1007/s10822-020-00289-y

Cited by 96 publications

(111 citation statements)

References 92 publications

(78 reference statements)

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“…During the D3R grand challenge 2, the core hopping transformation between ligands 91 and 93 could have been easily achieved by scaling and restraining, rather than the less rigorous approach that we improvised at that time 54 . Soft bonds would have been necessary to efficiently study the macrocycle perturbations with MS λ D in the D4R grand challenge 4 55 . Finally, scaling and restraining enables a broader scope of MS λ D multisite systems, because alchemical regions may be directly bonded to each other rather than requiring two intervening environment atoms.…”

Section: Discussionmentioning

confidence: 99%

A strategy for proline and glycine mutations to proteins with alchemical free energy calculations

Hayes

Brooks

2021

J Comput Chem

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Computation of the thermodynamic consequences of protein mutations holds great promise in protein biophysics and design. Alchemical free energy methods can give improved estimates of mutational free energies, and are already widely used in calculations of relative and absolute binding free energies in small molecule design problems. In principle, alchemical methods can address any amino acid mutation with an appropriate alchemical pathway, but identifying a strategy that produces such a path for proline and glycine mutations is an ongoing challenge. Most current strategies perturb only side chain atoms, while proline and glycine mutations also alter the backbone parameters and backbone ring topology. Some strategies also perturb backbone parameters and enable glycine mutations. This work presents a strategy that enables both proline and glycine mutations and comprises two key elements: a dual backbone with restraints and scaling of bonded terms, facilitating backbone parameter changes, and a soft bond in the proline ring, enabling ring topology changes in proline mutations. These elements also have utility for core hopping and macrocycle studies in computer‐aided drug design. This new strategy shows slight improvements over an alternative side chain perturbation strategy for a set T4 lysozyme mutations lacking proline and glycine, and yields good agreement with experiment for a set of T4 lysozyme proline and glycine mutations not previously studied. To our knowledge this is the first report comparing alchemical predictions of proline mutations with experiment. With this strategy in hand, alchemical methods now have access to the full palette of amino acid mutations.

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Section: Discussionmentioning

confidence: 99%

A strategy for proline and glycine mutations to proteins with alchemical free energy calculations

Hayes

Brooks

2021

J Comput Chem

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“…It may be that host-guest systems are "simple" enough that there is essentially nowhere for problems to hide, or confounding factors like polarizability and force field limitations may be more profound in these simple mini-receptors. Alternatively, performance of protein-ligand binding free energy calculations has often been worse in blind challenges like the SAMPL [18] and D3R [19][20][21][22] blind challenges than in the large-scale tests cited above, so it may be that typical retrospective tests simply benefit from participants utilizing additional knowledge which is not available prospectively or in blind challenges. This is supported to some extent by recent benchmarking work from Merck KGaA [13], and by an earlier industry perspective [23].…”

Section: Why Use Host Guest Systems?mentioning

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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Section: Why Use Host Guest Systems?mentioning

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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D3R grand challenge 4: blind prediction of protein–ligand poses, affinity rankings, and relative binding free energies

Cited by 96 publications

References 92 publications

A strategy for proline and glycine mutations to proteins with alchemical free energy calculations

A strategy for proline and glycine mutations to proteins with alchemical free energy calculations

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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