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.

scholarly journals Multi-Funnel Landscape of the Fold-Switching Protein RfaH-CTD

2017 ◽  
Author(s):  
Nathan A. Bernhardt ◽  
Ulrich H.E. Hansmann
Keyword(s):  
Free Energy ◽  
Transcription Factor ◽  
Biological Function ◽  
Double Helix ◽  
Energy Landscape ◽  
Three Dimensional ◽  
Conversion Process ◽  
Free Energy Landscape ◽  
Enhanced Sampling ◽  
Helix Bundle

AbstractProteins such as the transcription factor RfaH can change biological function by switching between distinct three-dimensional folds. RfaH regulates transcription if the C-terminal domain folds into a double helix bundle, and promotes translation when this domain assumes a β-barrel form. This fold-switch has been also observed for the isolated domain, dubbed by us RfaH-CTD, and is studied here with a variant of the RET approach recently introduced by us. We use the enhanced sampling properties of this technique to map the free energy landscape of RfaH-CTD and to propose a mechanism for the conversion process.TOC Image

scholarly journals Free-energy landscape of molecular interactions between endothelin 1 and human endothelin type B receptor: fly-casting mechanism

2019 ◽  
Vol 32 (7) ◽  
pp. 297-308 ◽  
Author(s):  
Junichi Higo ◽  
Kota Kasahara ◽  
Mitsuhito Wada ◽  
Bhaskar Dasgupta ◽  
Narutoshi Kamiya ◽  
...  
Keyword(s):  
Free Energy ◽  
Energy Landscape ◽  
Binding Pocket ◽  
Free Energy Landscape ◽  
Type B ◽  
Endothelin 1 ◽  
Reaction Coordinates ◽  
Explicit Solvent ◽  
Virtual System ◽  
G Protein Coupled

Abstract The free-energy landscape of interaction between a medium-sized peptide, endothelin 1 (ET1), and its receptor, human endothelin type B receptor (hETB), was computed using multidimensional virtual-system coupled molecular dynamics, which controls the system’s motions by introducing multiple reaction coordinates. The hETB embedded in lipid bilayer was immersed in explicit solvent. All molecules were expressed as all-atom models. The resultant free-energy landscape had five ranges with decreasing ET1–hETB distance: completely dissociative, outside-gate, gate, binding pocket, and genuine-bound ranges. In the completely dissociative range, no ET1–hETB interaction appeared. In the outside-gate range, an ET1–hETB attractive interaction was the fly-casting mechanism. In the gate range, the ET1 orientational variety decreased rapidly. In the binding pocket range, ET1 was in a narrow pathway with a steep free-energy slope. In the genuine-bound range, ET1 was in a stable free-energy basin. A G-protein-coupled receptor (GPCR) might capture its ligand from a distant place.

scholarly journals Neural Network Sampling of the Free Energy Landscape for Nitrogen Dissociation on Ruthenium

2020 ◽  
Author(s):  
Elizabeth Lee ◽  
Thomas Ludwig ◽  
Boyuan Yu ◽  
Aayush Singh ◽  
François Gygi ◽  
...  
Keyword(s):  
Neural Network ◽  
Free Energy ◽  
Heterogeneous Catalysis ◽  
Potential Energy ◽  
Potential Energy Surface ◽  
Energy Surface ◽  
Energy Landscape ◽  
Free Energy Landscape ◽  
Enhanced Sampling ◽  
Elementary Reactions

<p>Reaction rates in heterogeneous catalysis are predicted using the free energy profiles of elementary reactions. Conventionally, the energetics are computed from critical points of the potential energy surface, with harmonic free energy corrections. Here we use <i>ab initio</i> molecular dynamics and neural network-assisted enhanced sampling simulations to directly calculate the free energy landscape of a prototypical heterogeneous catalysis reaction, the dissociation of molecular nitrogen on ruthenium. We show that accelerating force- and frequency-based enhanced sampling using neural networks can characterize reactive phenomena at density functional theory-level accuracy. A previously reported molecularly adsorbed metastable state is found in the potential energy surface but is absent in the free energy surface. The potential of mean force for the dissociation reaction shows significant temperature-dependent effects beyond the standard harmonic approximation. We demonstrate that these thermodynamic effects can be important for elementary reactions on transition metal surfaces.</p>

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

Energetics and structural characterization of the “DFG-flip” conformational transition of B-RAF kinase: a SITS molecular dynamics study

2017 ◽  
Vol 19 (2) ◽  
pp. 1257-1267 ◽  
Author(s):  
Qiang Shao ◽  
Zhijian Xu ◽  
Jinan Wang ◽  
Jiye Shi ◽  
Weiliang Zhu
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Conformational Transition ◽  
Energy Landscape ◽  
Dynamics Simulation ◽  
Free Energy Landscape ◽  
Enhanced Sampling ◽  
Raf Kinase ◽  
Kinase A

A combination of a homology modeling technique and an enhanced sampling molecular dynamics simulation implemented using the SITS method is employed to compute a detailed map of the free-energy landscape and explore the conformational transition pathway of B-RAF kinase.

scholarly journals Neural Network Sampling of the Free Energy Landscape for Nitrogen Dissociation on Ruthenium

2020 ◽  
Author(s):  
Elizabeth Lee ◽  
Thomas Ludwig ◽  
Boyuan Yu ◽  
Aayush Singh ◽  
François Gygi ◽  
...  
Keyword(s):  
Neural Network ◽  
Free Energy ◽  
Heterogeneous Catalysis ◽  
Potential Energy ◽  
Potential Energy Surface ◽  
Energy Surface ◽  
Energy Landscape ◽  
Free Energy Landscape ◽  
Enhanced Sampling ◽  
Elementary Reactions

<p>Reaction rates in heterogeneous catalysis are predicted using the free energy profiles of elementary reactions. Conventionally, the energetics are computed from critical points of the potential energy surface, with harmonic free energy corrections. Here we use <i>ab initio</i> molecular dynamics and neural network-assisted enhanced sampling simulations to directly calculate the free energy landscape of a prototypical heterogeneous catalysis reaction, the dissociation of molecular nitrogen on ruthenium. We show that accelerating force- and frequency-based enhanced sampling using neural networks can characterize reactive phenomena at density functional theory-level accuracy. A previously reported molecularly adsorbed metastable state is found in the potential energy surface but is absent in the free energy surface. The potential of mean force for the dissociation reaction shows significant temperature-dependent effects beyond the standard harmonic approximation. We demonstrate that these thermodynamic effects can be important for elementary reactions on transition metal surfaces.</p>

scholarly journals Neural Network Sampling of the Free Energy Landscape for Nitrogen Dissociation on Ruthenium

2020 ◽  
Author(s):  
Elizabeth Lee ◽  
Thomas Ludwig ◽  
Boyuan Yu ◽  
Aayush Singh ◽  
François Gygi ◽  
...  
Keyword(s):  
Neural Network ◽  
Free Energy ◽  
Heterogeneous Catalysis ◽  
Potential Energy ◽  
Potential Energy Surface ◽  
Energy Surface ◽  
Energy Landscape ◽  
Free Energy Landscape ◽  
Enhanced Sampling ◽  
Elementary Reactions

<p>Reaction rates in heterogeneous catalysis are predicted using the free energy profiles of elementary reactions. Conventionally, the energetics are computed from critical points of the potential energy surface, with harmonic free energy corrections. Here we use <i>ab initio</i> molecular dynamics and neural network-assisted enhanced sampling simulations to directly calculate the free energy landscape of a prototypical heterogeneous catalysis reaction, the dissociation of molecular nitrogen on ruthenium. We show that accelerating force- and frequency-based enhanced sampling using neural networks can characterize reactive phenomena at density functional theory-level accuracy. A previously reported molecularly adsorbed metastable state is found in the potential energy surface but is absent in the free energy surface. The potential of mean force for the dissociation reaction shows significant temperature-dependent effects beyond the standard harmonic approximation. We demonstrate that these thermodynamic effects can be important for elementary reactions on transition metal surfaces.</p>

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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