Free-Energy Landscape of Protein–Ligand Interactions Coupled with Protein Structural Changes

2017 ◽  
Vol 121 (4) ◽  
pp. 731-740 ◽  
Author(s):  
Kei Moritsugu ◽  
Tohru Terada ◽  
Akinori Kidera
Keyword(s):  
Free Energy ◽  
Structural Changes ◽  
Energy Landscape ◽  
Free Energy Landscape ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

scholarly journals A Free-Energy Landscape Analysis of Calmodulin Obtained from an NMR Data-Utilized Multi-Scale Divide-and-Conquer Molecular Dynamics Simulation

Life ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1241
Author(s):  
Hiromitsu Shimoyama ◽  
Yasuteru Shigeta
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Structural Change ◽  
Conformational Changes ◽  
Calcium Binding ◽  
Structural Changes ◽  
Energy Landscape ◽  
Divide And Conquer ◽  
Free Energy Landscape ◽  
Multi Scale

Calmodulin (CaM) is a multifunctional calcium-binding protein, which regulates a variety of biochemical processes. CaM acts through its conformational changes and complex formation with its target enzymes. CaM consists of two globular domains (N-lobe and C-lobe) linked by an extended linker region. Upon calcium binding, the N-lobe and C-lobe undergo local conformational changes, followed by a major conformational change of the entire CaM to wrap the target enzyme. However, the regulation mechanisms, such as allosteric interactions, which regulate the large structural changes, are still unclear. In order to investigate the series of structural changes, the free-energy landscape of CaM was obtained by multi-scale divide-and-conquer molecular dynamics (MSDC-MD). The resultant free-energy landscape (FEL) shows that the Ca2+ bound CaM (holo-CaM) would take an experimentally famous elongated structure, which can be formed in the early stage of structural change, by breaking the inter-domain interactions. The FEL also shows that important interactions complete the structural change from the elongated structure to the ring-like structure. In addition, the FEL might give a guiding principle to predict mutational sites in CaM. In this study, it was demonstrated that the movement process of macroscopic variables on the FEL may be diffusive to some extent, and then, the MSDC-MD is suitable to the parallel computation.

scholarly journals Non-affine displacements encode collective conformational fluctuations in proteins

2019 ◽  
Author(s):  
Dube Dheeraj Prakashchand ◽  
Navjeet Ahalawat ◽  
Satyabrata Bandyopadhyay ◽  
Surajit Sengupta ◽  
Jagannath Mondal
Keyword(s):  
Free Energy ◽  
Structural Changes ◽  
Energy Landscape ◽  
Conformational Transitions ◽  
Free Energy Landscape ◽  
Native Structure ◽  
Markov State Model ◽  
Markov State ◽  
Hierarchical Complexity ◽  
Kinetics Of

AbstractIdentifying subtle conformational fluctuations underlying the dynamics of bio macro-molecules is crucial for resolving their free energy landscape. We show that a collective variable, originally proposed for crystalline solids, is able to filter out essential macro-molecular motions more efficiently than other approaches. While homogenous or ‘affine’ deformations of the biopolymer are trivial, biopolymer conformations are complicated by the occurrence of in-homogenous or ‘non-affine’ displacements of atoms relative to their positions in the native structure. We show that these displacements encode functionally relevant conformations of macromolecule and, in combination with a formalism based upon time-structured independent component analysis, quantitatively resolve the free energy landscape of a number of macromolecules of hierarchical complexity. The kinetics of conformational transitions among the basins can now be mapped within the framework of a Markov state model. The non-affine modes, obtained by projecting out homogenous fluctuations from the local displacements, are found to be responsible for local structural changes required for transitioning between pairs of macro states.

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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