Validation of tautomeric and protomeric binding modes by free energy calculations. A case study for the structure based optimization of d-amino acid oxidase inhibitors

2018 ◽  
Vol 32 (2) ◽  
pp. 331-345 ◽  
Author(s):  
Zoltán Orgován ◽  
György G. Ferenczy ◽  
Thomas Steinbrecher ◽  
Bence Szilágyi ◽  
Dávid Bajusz ◽  
...  
Keyword(s):  
Free Energy ◽  
Amino Acid ◽  
Free Energy Calculations ◽  
Acid Oxidase ◽  
Binding Modes ◽  
Amino Acid Oxidase ◽  
Energy Calculations

scholarly journals Insights from Free-Energy Calculations: Protein Conformational Equilibrium, Driving Forces, and Ligand-Binding Modes

2012 ◽  
Vol 103 (2) ◽  
pp. 342-351 ◽  
Author(s):  
Yu-ming M. Huang ◽  
Wei Chen ◽  
Michael J. Potter ◽  
Chia-en A. Chang
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Conformational Equilibrium ◽  
Driving Forces ◽  
Free Energy Calculations ◽  
Binding Modes ◽  
Energy Calculations

Predicting Binding Modes from Free Energy Calculations

2008 ◽  
Vol 51 (9) ◽  
pp. 2657-2667 ◽  
Author(s):  
Martin Nervall ◽  
Peter Hanspers ◽  
Jens Carlsson ◽  
Lars Boukharta ◽  
Johan Åqvist
Keyword(s):  
Free Energy ◽  
Free Energy Calculations ◽  
Binding Modes ◽  
Energy Calculations

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

2019 ◽  
Author(s):  
Willem Jespers ◽  
Grégory Verdon ◽  
Jhonny Azuaje ◽  
maria majellaro ◽  
Henrik Keränen ◽  
...  
Keyword(s):  
Free Energy ◽  
Adenosine Receptor ◽  
Free Energy Calculations ◽  
Binding Modes ◽  
A2a Adenosine Receptor ◽  
Binding Model ◽  
Energy Calculations ◽  
X Ray ◽  
X Ray Crystallography ◽  
Pharmacological Data

<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>

scholarly journals Microscopic Characterization of the Chloride Permeation Pathway in the Human Excitatory Amino Acid Transporter 1 (EAAT1)

2021 ◽  
Author(s):  
Shashank Pant ◽  
Qianyi Wu ◽  
Renae M Ryan ◽  
Emad Tajkhorshid
Keyword(s):  
Free Energy ◽  
Amino Acid ◽  
Conformational Changes ◽  
Large Scale ◽  
Excitatory Amino Acid ◽  
Free Energy Calculations ◽  
Amino Acid Transporters ◽  
Coupled Transport ◽  
Energy Calculations ◽  
Transport Cycle

Excitatory amino acid transporters (EAATs) are glutamate transporters that belong to the solute carrier 1A (SLC1A) family. They couple glutamate transport to the co-transport of three sodium (Na+) ions and one proton (H+) and the counter-transport of one potassium (K+) ion. In addition to this coupled transport, binding of substrate and Na+ ions to EAATs activates a thermodynamically uncoupled chloride (Cl-) conductance. Structures of SLC1A family members have revealed that these transporters use a twisting elevator mechanism of transport, where a mobile transport domain carries substrate and coupled ions across the membrane, while a static scaffold domain anchors the transporter in the membrane. We have recently demonstrated that the uncoupled Cl- conductance is activated by the formation of an aqueous pore at the domain interface during the transport cycle in archaeal GltPh. However, a pathway for the uncoupled Cl- conductance has not been reported for the EAATs and it is unclear if such a pathway is conserved. Here, we employ all-atom molecular dynamics (MD) simulations combined with enhanced sampling, free-energy calculations, and experimental mutagenesis to approximate large-scale conformational changes during the transport process and identified a Cl- conducting conformation in human EAAT1. We were able to extensively sample the large-scale structural transitions, allowing us to capture an intermediate conformation formed during the transport cycle with a continuous aqueous pore at the domain interface. The free-energy calculations performed for the conduction of Cl- and Na+ ions through the captured conformation, highlight the presence of two hydrophobic gates which control the selective movement of Cl- through the aqueous pathway. Overall, our findings provide insights into the mechanism by which a human glutamate transporter can support the dual functions of active transport and passive Cl- permeation and confirming the commonality of this mechanism in different members of the SLC1A family.

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