scholarly journals The Activation of c-Src Tyrosine Kinase: Conformational Transition Pathway and Free Energy Landscape

2016 ◽  
Vol 121 (15) ◽  
pp. 3352-3363 ◽  
Author(s):  
Mikolai Fajer ◽  
Yilin Meng ◽  
Benoît Roux
Keyword(s):  
Free Energy ◽  
Tyrosine Kinase ◽  
Conformational Transition ◽  
Energy Landscape ◽  
Free Energy Landscape ◽  
Src Tyrosine Kinase

scholarly journals Free energy landscape for the entire transport cycle of triose-phosphate/phosphate translocator

2017 ◽  
Author(s):  
Mizuki Takemoto ◽  
Yongchan Lee ◽  
Ryuichiro Ishitani ◽  
Osamu Nureki
Keyword(s):  
Free Energy ◽  
Conformational Changes ◽  
Conformational Transition ◽  
Substrate Binding ◽  
Energy Landscape ◽  
Umbrella Sampling ◽  
Free Energy Landscape ◽  
Coupling Mechanism ◽  
Triose Phosphate ◽  
Phosphate Translocator

AbstractSecondary active transporters translocate their substrates using the electrochemical potentials of other chemicals, undergoing large-scale conformational changes. Despite extensive structural studies, the atomic details of the transport mechanism still remain elusive. Here we performed a series of all-atom molecular dynamics simulations of the triose-phosphate/phosphate translocator (TPT), which exports organic phosphates in the chloroplast stroma in strict counter exchange with inorganic phosphate (Pi). Biased sampling methods, including string method and umbrella sampling, successfully reproduced the conformational changes between the inward– and outward-facing states, along with the substrate binding. The free energy landscape of this entire TPT transition pathway demonstrated the alternating access and substrate translocation mechanisms, which revealed Pi is relayed by positively charged residues along the transition pathway. Furthermore, the conserved Glu207 functions as a “molecular switch”, linking the local substrate binding and the global conformational transition. Our results provide atomic-detailed insights into the energy coupling mechanism of antiporter.

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 Real-time observation of ligand-induced allosteric transitions in a PDZ domain

2020 ◽  
Vol 117 (42) ◽  
pp. 26031-26039 ◽  
Author(s):  
Olga Bozovic ◽  
Claudio Zanobini ◽  
Adnan Gulzar ◽  
Brankica Jankovic ◽  
David Buhrke ◽  
...  
Keyword(s):  
Free Energy ◽  
Binding Affinity ◽  
Conformational Transition ◽  
Energy Landscape ◽  
Pdz Domain ◽  
Free Energy Landscape ◽  
Peptide Ligand ◽  
Dynamical Process ◽  
Time Observation ◽  
Dynamics Simulations

While allostery is of paramount importance for protein regulation, the underlying dynamical process of ligand (un)binding at one site, resulting time evolution of the protein structure, and change of the binding affinity at a remote site are not well understood. Here the ligand-induced conformational transition in a widely studied model system of allostery, the PDZ2 domain, is investigated by transient infrared spectroscopy accompanied by molecular dynamics simulations. To this end, an azobenzene-derived photoswitch is linked to a peptide ligand in a way that its binding affinity to the PDZ2 domain changes upon switching, thus initiating an allosteric transition in the PDZ2 domain protein. The subsequent response of the protein, covering four decades of time, ranging from ∼1 ns to ∼μs, can be rationalized by a remodeling of its rugged free-energy landscape, with very subtle shifts in the populations of a small number of structurally well-defined states. It is proposed that structurally and dynamically driven allostery, often discussed as limiting scenarios of allosteric communication, actually go hand-in-hand, allowing the protein to adapt its free-energy landscape to incoming signals.

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>

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
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