Q6: A comprehensive toolkit for empirical valence bond and related free energy calculations

Bauer, Paul; Barrozo, Alexandre; Purg, Miha; Amrein, Beat Anton; Esguerra, Mauricio; Wilson, Philippe B.; Major, Dan Thomas; Åqvist, Johan; Kamerlin, Shina Caroline Lynn

doi:10.1016/j.softx.2017.12.001

Cited by 61 publications

(73 citation statements)

References 94 publications

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“…The receptor-ligand structures in the equilibrated membrane were then transferred to the MD package Q, in order to perform FEP calculations under spherical boundary conditions. 5,6 A 50 Å diameter sphere was centered on the center of geometry of ZM241385 (or equivalent point in the remaining structures), where solvent atoms are subject to polarization and radial restrains using the surface constrained all-atom solvent (SCAAS) model to mimic the properties of bulk water at the sphere surface. 5,51 Atoms lying outside the simulation sphere are tightly constrained (200 kcal/mol/Å 2 force constant) and excluded from the calculation of non-bonded interactions.…”

Section: N Conclusionmentioning

confidence: 99%

“…[4][5][6] The combination of both ligand and residue FEP simulations can provide a full energetic landscape of the molecular interactions governing protein-ligand binding, which underlies the design of two complementary protocols in our lab, namely QligFEP 3 and QresFEP 4 , integrated in the molecular dynamics (MD) software package Q. 5,6 One area where this approach is particularly promising is the design of ligands for G-protein coupled receptors (GPCRs), a superfamily of seven-transmembrane (7TM) cellular receptors 7 that mediate the therapeutic effects of about 30% of all marketed drugs. 8 The extensive structureactivity relationship (SAR) and site-directed mutagenesis (SDM) data available can be combined with the increasing growth of structural knowledge of many GPCR targets.…”

Section: N Introductionmentioning

confidence: 99%

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X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

Jespers¹,

Verdon²,

Azuaje³

et al. 2019

Preprint

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<div> <div> <div> <p>Nowadays, rigorous free energy calculations are routinely considered in pharmaceutical design strategies. One typical sce- nario is the lead-optimization based on well-defined protein-ligand binding modes, inferred by pharmacological data in com- putational models and ultimately revealed by structural data. In this work, we reveal the molecular determinants of antago- nist binding to the adenosine A2A adenosine receptor (AR), an emerging target in immuno-oncology, via a robust protocol that connects structural and pharmacological data through free energy perturbation (FEP) calculations. Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed with FEP simulations of each side-chain mutation, performed on alternate binding modes previously proposed in the literature. The results strongly suggested that only one binding mode could explain this experimental data, which was used to subsequently design a series of 11 chromone deriva- tives. The experimental affinities of these new compounds were linked through a cycle of ligand-FEP calculations around selected ligand pairs, which allowed the identification of the optimal positioning of the different chemical substituents in the proposed binding model. Subsequent X-ray crystallography of the A2AAR with a low and high affinity chromone derivative confirmed the predicted binding orientation, and provided new insights in the role of the explored substituents in the chro- </p> </div> </div> <div> <div> <p>mone scaffold. </p> </div> </div> </div>

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Section: N Conclusionmentioning

confidence: 99%

Section: N Introductionmentioning

confidence: 99%

X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

Jespers¹,

Verdon²,

Azuaje³

et al. 2019

Preprint

Self Cite

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“…An EVB implementation is available within the MOLARIS package . More recently, EVB has also been made available in CHARMM, TINKER, and Q6 . Temporal MS‐ARMD and MS‐ARMD based on energy mixing have been implemented in CHARMM.…”

Section: Computational Techniquesmentioning

confidence: 99%

“…137 More recently, EVB has also been made available in CHARMM, 33 TINKER, 138 and Q6. 139 Temporal MS-ARMD 47,50 and MS-ARMD based on energy mixing 60 have been implemented in CHARMM. MMPT 66 and MS-ARMD with VALBOND 62,65 (for metal force fields) are also available within CHARMM.…”

Section: Existing Implementationsmentioning

confidence: 99%

Reactive molecular dynamics: From small molecules to proteins

Meuwly

2018

WIREs Comput Mol Sci

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The current status of reactive molecular dynamics (MD) simulations is summarized. Both, methodological aspects and applications to problems ranging from gas phase reaction dynamics to ligand‐binding in solvated proteins are discussed, focusing on extracting information from simulations that cannot easily be obtained from experiments alone. One specific example is the structural interpretation of the ligand rebinding time scales extracted from state‐of‐the art time‐resolved experiments. Atomistic simulations employing validated reactive interaction potentials are capable of providing structural information about the time scales involved. Both, merits and shortcomings of the various methods are discussed and the outlook summarizes possible future avenues such as reactive potentials based on machine learning techniques. This article is categorized under: Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Theoretical and Physical Chemistry > Reaction Dynamics and Kinetics Molecular and Statistical Mechanics > Molecular Interactions

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“…[3][4][5] Thec ombination of both ligand and residue FEP simulations can provide af ull energetic landscape of the molecular interactions governing protein-ligand binding,w hich underlies the design of two complementary protocols in our lab,n amely QligFEP [6] and QresFEP, [3] integrated in the molecular dynamics (MD) software package Q. [7,8] One area where this approach is particularly promising is the design of ligands for G-protein-coupled receptors (GPCRs), as uperfamily of seven-transmembrane (7TM) cellular receptors [9] that mediate the therapeutic effects of about 30 %ofall marketed drugs. [10] There is alarge amount of SAR and SDM data available for these receptors,w hich can be combined with the increasing growth of structural knowledge of many GPCR targets.T he first integrated approach of ligand and residue FEP simulations was published by Boukharta et al to characterize antagonist binding to the Y 1 neuropeptide receptor, [11] which we later expanded to other GPCR families,i ncluding the related neuropeptide receptor Y 2 , [12] the orphan receptor GPR139 [13] and several members of the family of adenosine receptors.…”

Section: Introductionmentioning

confidence: 99%

X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A_2A Adenosine Receptor Antagonists

et al. 2020

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We present a robust protocol based on iterations of free energy perturbation (FEP) calculations, chemical synthesis, biophysical mapping and X‐ray crystallography to reveal the binding mode of an antagonist series to the A2A adenosine receptor (AR). Eight A2AAR binding site mutations from biophysical mapping experiments were initially analyzed with sidechain FEP simulations, performed on alternate binding modes. The results distinctively supported one binding mode, which was subsequently used to design new chromone derivatives. Their affinities for the A2AAR were experimentally determined and investigated through a cycle of ligand‐FEP calculations, validating the binding orientation of the different chemical substituents proposed. Subsequent X‐ray crystallography of the A2AAR with a low and a high affinity chromone derivative confirmed the predicted binding orientation. The new molecules and structures here reported were driven by free energy calculations, and provide new insights on antagonist binding to the A2AAR, an emerging target in immuno‐oncology.

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Q6: A comprehensive toolkit for empirical valence bond and related free energy calculations

Cited by 61 publications

References 94 publications

X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

Reactive molecular dynamics: From small molecules to proteins

X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A_2A Adenosine Receptor Antagonists

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Q6: A comprehensive toolkit for empirical valence bond and related free energy calculations

Cited by 61 publications

References 94 publications

X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

X-Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

Reactive molecular dynamics: From small molecules to proteins

X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A2A Adenosine Receptor Antagonists

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X‐Ray Crystallography and Free Energy Calculations Reveal the Binding Mechanism of A_2A Adenosine Receptor Antagonists