Detecting Ligand-Binding Events and Free Energy Landscape while Imaging Membrane Receptors at Subnanometer Resolution

Nano Letters ◽  
2017 ◽  
Vol 17 (5) ◽  
pp. 3261-3269 ◽  
Author(s):  
Moritz Pfreundschuh ◽  
Daniel Harder ◽  
Zöhre Ucurum ◽  
Dimitrios Fotiadis ◽  
Daniel J. Müller
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Energy Landscape ◽  
Membrane Receptors ◽  
Free Energy Landscape

The Perturbed Free Energy Landscape: Linking Ligand Binding to Biomolecular Folding

ChemBioChem ◽  
2020 ◽  
Author(s):  
fareed aboul-ela ◽  
Abdallah S Abdelsatter ◽  
Youssef Mansour
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
Energy Landscape ◽  
Free Energy Landscape

scholarly journals Imaging G protein–coupled receptors while quantifying their ligand-binding free-energy landscape

2015 ◽  
Vol 12 (9) ◽  
pp. 845-851 ◽  
Author(s):  
David Alsteens ◽  
Moritz Pfreundschuh ◽  
Cheng Zhang ◽  
Patrizia M Spoerri ◽  
Shaun R Coughlin ◽  
...  
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
G Protein ◽  
Binding Free Energy ◽  
Energy Landscape ◽  
G Protein Coupled Receptors ◽  
Free Energy Landscape ◽  
G Protein Coupled

scholarly journals Free energy calculations of the functional selectivity of 5-HT2B G protein-coupled receptor

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0243313
Author(s):  
Brandon L. Peters ◽  
Jinxia Deng ◽  
Andrew L. Ferguson
Keyword(s):  
Free Energy ◽  
Ligand Binding ◽  
G Protein ◽  
Intracellular Signaling ◽  
Serotonin Receptor ◽  
Energy Landscape ◽  
Free Energy Calculations ◽  
Free Energy Landscape ◽  
Functional Selectivity ◽  
G Protein Coupled

G Protein-Coupled Receptors (GPCRs) mediate intracellular signaling in response to extracellular ligand binding and are the target of one-third of approved drugs. Ligand binding modulates the GPCR molecular free energy landscape by preferentially stabilizing active or inactive conformations that dictate intracellular protein recruitment and downstream signaling. We perform enhanced sampling molecular dynamics simulations to recover the free energy surfaces of a thermostable mutant of the GPCR serotonin receptor 5-HT2B in the unliganded form and bound to a lysergic acid diethylamide (LSD) agonist and lisuride antagonist. LSD binding imparts a ∼110 kJ/mol driving force for conformational rearrangement into an active state. The lisuride-bound form is structurally similar to the apo form and only ∼24 kJ/mol more stable. This work quantifies ligand-induced conformational specificity and functional selectivity of 5-HT2B and presents a platform for high-throughput virtual screening of ligands and rational engineering of the ligand-bound molecular free energy landscape.

scholarly journals Chasing the full free energy landscape of neuroreceptor/ligand unbinding by metadynamics simulations

2019 ◽  
Author(s):  
Riccardo Capelli ◽  
Anna Bochicchio ◽  
GiovanniMaria Piccini ◽  
Rodrigo Casasnovas ◽  
Paolo Carloni ◽  
...  
Keyword(s):  
Free Energy ◽  
Sampling Method ◽  
Energy Landscape ◽  
Membrane Receptors ◽  
Free Energy Landscape ◽  
Neuronal Membrane ◽  
Allosteric Modulator ◽  
Enhanced Sampling ◽  
Reaction Coordinates ◽  
Slowing Down

Predicting the complete free energy landscape associated with protein-ligand unbinding would greatly help designing drugs with highly optimized pharmacokinetics. Here we investigate the unbinding of the iperoxo agonist to its target human neuroreceptor M2, embedded in a neuronal membrane. By feeding out-of-equilibrium molecular simulations data in a classification analysis, we identify the few essential reaction coordinates of the process. The full landscape is then reconstructed using an exact enhanced sampling method, well-tempered metadynamics in its funnel variant. The calculations reproduce well the measured affinity, provide a rationale for mutagenesis data and show that the ligand can escape via two different routes. The allosteric modulator LY2119620 turns out to hamper both escapes routes, thus slowing down the unbinding process, as experimentally observed. This computationally affordable protocol is totally general and it can be easily applied to determine the full free energy landscape of membrane receptors/drug interactions.

Determination of Base Flipping Free Energy Landscapes from Nonequilibrium Stratification

2019 ◽  
Author(s):  
Xiaohui Wang ◽  
Zhaoxi Sun
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Sampling Technique ◽  
Umbrella Sampling ◽  
Energy Simulation ◽  
Nonlinear Dependence ◽  
Free Energy Landscape ◽  
Convergence Criterion ◽  
Base Flipping ◽  
Convergence Behavior

<p>Correct calculation of the variation of free energy upon base flipping is crucial in understanding the dynamics of DNA systems. The free energy landscape along the flipping pathway gives the thermodynamic stability and the flexibility of base-paired states. Although numerous free energy simulations are performed in the base flipping cases, no theoretically rigorous nonequilibrium techniques are devised and employed to investigate the thermodynamics of base flipping. In the current work, we report a general nonequilibrium stratification scheme for efficient calculation of the free energy landscape of base flipping in DNA duplex. We carefully monitor the convergence behavior of the equilibrium sampling based free energy simulation and the nonequilibrium stratification and determine the empirical length of time blocks required for converged sampling. Comparison between the performances of equilibrium umbrella sampling and nonequilibrium stratification is given. The results show that nonequilibrium free energy simulation is able to give similar accuracy and efficiency compared with the equilibrium enhanced sampling technique in the base flipping cases. We further test a convergence criterion we previously proposed and it comes out that the convergence behavior determined by this criterion agrees with those given by the time-invariant behavior of PMF and the nonlinear dependence of standard deviation on the sample size. </p>

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