Dehydron Analysis: Quantifying the Effect of Hydrophobic Groups on the Strength and Stability of Hydrogen Bonds

Fraser, Christopher M.; Fernández, Ariel; Scott, L. Ridgway

doi:10.1007/978-1-4419-5913-3_53

Cited by 9 publications

(11 citation statements)

References 47 publications

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“…As shown in several studies, strong hydrogen bonds are important for fragment anchoring, whereas a hydrophobic environment can be important for the stabilization of hydrogen bonds. 23,37,38 Thus, the overlap of a fragment with a low-energy protein hot spot defined by both polar and apolar interaction energies, as suggested previously, 7 together with the involvement of a fragment in strong protein interactions can give an indication about the conservation or variability of its binding mode when part of a drug-like ligand. Finally, we explored whether structural properties of fragments and additives are indicative of a conserved binding mode.…”

Section: ■ Results and Discussionmentioning

confidence: 76%

Do Fragments and Crystallization Additives Bind Similarly to Drug-like Ligands?

Drwal

Jacquemard

Cruz

et al. 2017

J. Chem. Inf. Model.

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The success of fragment-based drug design (FBDD) hinges upon the optimization of low-molecular-weight compounds (MW < 300 Da) with weak binding affinities to lead compounds with high affinity and selectivity. Usually, structural information from fragment-protein complexes is used to develop ideas about the binding mode of similar but drug-like molecules. In this regard, crystallization additives such as cryoprotectants or buffer components, which are highly abundant in crystal structures, are frequently ignored. Thus, the aim of this study was to investigate the information present in protein complexes with fragments as well as those with additives and how they relate to the binding modes of their drug-like counterparts. We present a thorough analysis of the binding modes of crystallographic additives, fragments, and drug-like ligands bound to four diverse targets of wide interest in drug discovery and highly represented in the Protein Data Bank: cyclin-dependent kinase 2, β-secretase 1, carbonic anhydrase 2, and trypsin. We identified a total of 630 unique molecules bound to the catalytic binding sites, among them 31 additives, 222 fragments, and 377 drug-like ligands. In general, we observed that, independent of the target, protein-fragment interaction patterns are highly similar to those of drug-like ligands and mostly cover the residues crucial for binding. Crystallographic additives are also able to show conserved binding modes and recover the residues important for binding in some of the cases. Moreover, we show evidence that the information from fragments and drug-like ligands can be applied to rescore docking poses in order to improve the prediction of binding modes.

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Section: ■ Results and Discussionmentioning

confidence: 76%

Do Fragments and Crystallization Additives Bind Similarly to Drug-like Ligands?

Drwal

Jacquemard

Cruz

et al. 2017

J. Chem. Inf. Model.

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“…They are important features in protein−protein complexation, protein−ligand interactions, high level structural arrangement, and other biochemical phenomena and bioinformatical applications such as measuring proteomic complexity and selective inhibitor design. 29,31,34 These examples support and motivate the goal of understanding the specific hydration of protein binding sites. Although dehydrons are specific to hydrogen bonding near the protein backbone, one would expect to find both analogous and alternative hydration features near other protein side chains.…”

Section: ■ Introductionmentioning

confidence: 67%

Large-Scale Study of Hydration Environments through Hydration Sites

et al. 2019

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Hydration sites are locations of interest to water and they can be used to classify the behaviour of water around chemical motifs commonly found on the surface of proteins.Inhomogeneous uid solvation theory (IFST) is a method for calculating hydration free energy changes from molecular dynamics (MD) trajectories. In this paper hydration sites are identied from MD simulations of 380 diverse protein structures. The hydration free energies of the hydration sites are calculated using IFST and distributions of these free energy changes are analysed. The results show that for some hydration sites near features conventionally regarded as attractive to water, such as hydrogen bond donors, the water molecules are actually relatively weakly bound and are easily displaced. We also construct plots of the spatial density of hydration sites with high medium and low 1 hydration free energy changes which represent weakly and strongly bound hydration sites. It is found that these plots show consistent features around common polar amino acids for all of the proteins studied.

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“…In addition to the inter-loop contact between Ser93 and Gly207, in the sample frame we observe a CDR3α-CDR3α hydrogen bond between Ser93 and the backbone of Gly94, as well as three CDR3β-CDR3β intra-loop hydrogen bonds between Thr209 and Gly206 (Figure 6A ). Surrounding these hydrogen bonds are numerous hydrophobic residues that can shield the hydrogen bonds from solvent, which has been shown to enhance stability in other contexts (Fraser et al, 2010 , 2011 ). There are nine hydrophobic residues within 6 angstroms of either Ser93 or Gly207, creating a hydrophobic shell around the inter-loop hydrogen bond and shielding some of the intra-loop interactions as well.…”

Section: Resultsmentioning

confidence: 99%

The Hypervariable Loops of Free TCRs Sample Multiple Distinct Metastable Conformations in Solution

Crooks

Boughter

Scott

et al. 2018

Front. Mol. Biosci.

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CD4+ and CD8+ αβ T cell antigen recognition is determined by the interaction between the TCR Complementarity Determining Region (CDR) loops and the peptide-presenting MHC complex. These T cells are known for their ability to recognize multiple pMHC complexes, and for a necessary promiscuity that is required for their selection and function in the periphery. Crystallographic studies have previously elucidated the role of structural interactions in TCR engagement, but our understanding of the dynamic process that occurs during TCR binding is limited. To better understand the dynamic states that exist for TCR CDR loops in solution, and how this relates to their states when in complex with pMHC, we simulated the 2C T cell receptor in solution using all-atom molecular dynamics in explicit water and constructed a Markov State Model for each of the CDR3α and CDR3β loops. These models reveal multiple metastable states for the CDR3 loops in solution. Simulation data and metastable states reproduce known CDR3β crystal conformations, and reveal several novel conformations suggesting that CDR3β bound states are the result of search processes from nearby pre-existing equilibrium conformational states. Similar simulations of the invariant, Type I Natural Killer T cell receptor NKT15, which engages the monomorphic, MHC-like CD1d ligand, demonstrate that iNKT TCRs also have distinct states, but comparatively restricted degrees of motion.

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Dehydron Analysis: Quantifying the Effect of Hydrophobic Groups on the Strength and Stability of Hydrogen Bonds

Cited by 9 publications

References 47 publications

Do Fragments and Crystallization Additives Bind Similarly to Drug-like Ligands?

Do Fragments and Crystallization Additives Bind Similarly to Drug-like Ligands?

Large-Scale Study of Hydration Environments through Hydration Sites

The Hypervariable Loops of Free TCRs Sample Multiple Distinct Metastable Conformations in Solution

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