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Yuko Okamoto - One of the best experts on this subject based on the ideXlab platform.
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implementation of replica exchange Umbrella Sampling in gamess
Computer Physics Communications, 2018Co-Authors: Shingo Ito, Dmitri G Fedorov, Yuko Okamoto, Stephan IrleAbstract:Abstract In GAMESS-US quantum chemistry package, both replica-exchange molecular dynamics (REMD) and the Umbrella Sampling (US) methods are available. However, prior to this work, the replica-exchange Umbrella Sampling (REUS) method, combining REMD and US, was not implemented. REUS affords a more efficient conformational Sampling than the conventional US method and is often used in MD simulations. We implemented REUS in GAMESS-US and improved some routines of the existing REMD code. A density-functional tight-binding REMD (DFTB-REMD) simulation of alanine deca-peptide and a DFTB-MD REUS simulation of proton transfer in malonaldehyde were performed. The results of DFTB-MD REUS simulations performed with three different simulation packages were compared to validate our GAMESS-US implementation.
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computational analysis for selectivity of histone deacetylase inhibitor by replica exchange Umbrella Sampling molecular dynamics simulations
Journal of Chemical Physics, 2018Co-Authors: Shuichiro Tsukamoto, Yoshitake Sakae, Yukihiro Itoh, Takayoshi Suzuki, Yuko OkamotoAbstract:We performed protein-ligand docking simulations with a ligand T247, which has been reported as a selective inhibitor of a histone deacetylase HDAC3, by the replica-exchange Umbrella Sampling method in order to estimate the free energy profiles along ligand docking pathways of HDAC3-T247 and HDAC2-T247 systems. The simulation results showed that the docked state of the HDAC3-T247 system is more stable than that of the HDAC2-T247 system although the amino-acid sequences and structures of HDAC3 and HDAC2 are very similar. By comparing structures obtained from the simulations of both systems, we found the difference between structures of hydrophobic residues at the entrance of the catalytic site. Moreover, we performed conventional molecular dynamics simulations of HDAC3 and HDAC2 systems without T247, and the results also showed the same difference of the hydrophobic structures. Therefore, we consider that this hydrophobic structure contributes to the stabilization of the docked state of the HDAC3-T247 system. Furthermore, we show that Tyr209, which is one of the hydrophobic residues in HDAC2, plays a key role in the instability from the simulation results of a mutated-HDAC2 system.
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implementation of replica exchange Umbrella Sampling in the dftb semiempirical quantum chemistry package
Computer Physics Communications, 2016Co-Authors: Shingo Ito, Stephan Irle, Yuko OkamotoAbstract:Abstract The replica-exchange Umbrella Sampling (REUS) method combines replica-exchange and Umbrella Sampling methods and allows larger conformational Sampling than conventional simulation methods. This method has been used in many studies to understand docking mechanisms and the functions of molecules. However, REUS has not been combined with quantum chemical codes. Therefore, we implemented the REUS simulation technique in the DFTB + quantum chemistry code utilizing approximate density functional theory. We performed REUS simulations of an intra-molecular proton transfer reaction of malonaldehyde and a formation of a phthalocyanine from four phthalonitriles and one iron atom to validate the reliability of our implemented REUS–DFTB + combination.
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prediction of protein ligand binding structures by replica exchange Umbrella Sampling simulations application to kinase systems
Journal of Chemical Theory and Computation, 2013Co-Authors: Hironori Kokubo, Toshimasa Tanaka, Yuko OkamotoAbstract:We have applied our prediction method, which is based on the replica-exchange Umbrella Sampling for protein-ligand binding structures, to two kinase systems (p38 and JNK3) with two different ligand molecules for each kinase. Starting from configurations in which the protein and the ligand are far away from each other, our method predicted the ligand binding structures in excellent agreement with the experimental data from PDB in all four cases, which suggests the general applicability of our method to kinase systems. In addition, the protein flexibility was shown to be essential to predict the correct binding structure for one of the systems, where dihydroquinolinone was bound to p38 alpha kinase (PDB ID: 1OVE ).
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free energy analyses of a proton transfer reaction by simulated tempering Umbrella Sampling and first principles molecular dynamics simulations
Physical Review E, 2013Co-Authors: Yoshiharu Mori, Yuko OkamotoAbstract:A simulated tempering method, which is referred to as simulated-tempering Umbrella Sampling, for calculating the free energy of chemical reactions is proposed. First principles molecular dynamics simulations with this simulated tempering were performed to study the intramolecular proton transfer reaction of malonaldehyde in an aqueous solution. Conformational Sampling in reaction coordinate space can be easily enhanced with this method, and the free energy along a reaction coordinate can be calculated accurately. Moreover, the simulated-tempering Umbrella Sampling provides trajectory data more efficiently than the conventional Umbrella Sampling method.
Martin Karplus - One of the best experts on this subject based on the ideXlab platform.
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Gaussian-mixture Umbrella Sampling.
The journal of physical chemistry. B, 2009Co-Authors: Paul Maragakis, Arjan Van Der Vaart, Martin KarplusAbstract:We introduce the Gaussian-mixture Umbrella Sampling method (GAMUS) , a biased molecular dynamics technique based on adaptive Umbrella Sampling that efficiently escapes free energy minima in multidimensional problems. The prior simulation data are reweighted with a maximum likelihood formulation, and the new approximate probability density is fit to a Gaussian-mixture model, augmented by information about the unsampled areas. The method can be used to identify free energy minima in multidimensional reaction coordinates. To illustrate GAMUS , we apply it to the alanine dipeptide (2D reaction coordinate) and tripeptide (4D reaction coordinate).
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determination of equilibrium properties of biomolecular systems using multidimensional adaptive Umbrella Sampling
Journal of Chemical Physics, 1999Co-Authors: Christian Bartels, Michael Schaefer, Martin KarplusAbstract:Two-dimensional adaptive Umbrella Sampling with the first Umbrella coordinate equal to the potential energy of the system and the second Umbrella coordinate equal to a function that discriminates important folded conformations from unfolded conformations is used to determine the equilibrium properties of complex biological systems. Compared to one-dimensional adaptive Umbrella Sampling with the potential energy as Umbrella coordinate (multicanonical Sampling), more reliable results can be obtained in certain cases. The method is applied to a helical peptide (RN24) with an analytical continuum solvent potential in combination with the PARAM19 force field of CHARMM. This effective potential energy function has been shown to describe the structural preferences of solvated peptides. With the two-dimensional approach and the deviation from the helical structure as the second Umbrella coordinate, a converged description of the structural properties and the thermodynamics of the peptide RN24 is obtained. In particular, we find that the formation of the helix of RN24 occurs as a transition accompanied by a characteristic peak in the heat capacity. A formalism is described that uses the weighting factors obtained from a self-consistent solution of the weighted histogram analysis method equations to combine the results from a series of simulations with different biases and calculate the ensemble average of any dynamical variable as a function of the temperature without the need for extracting the density of states from the simulations. It is shown how the formalism can be used to calculate thermodynamic properties of the system.
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probability distributions for complex systems adaptive Umbrella Sampling of the potential energy
Journal of Physical Chemistry B, 1998Co-Authors: Christian Bartels And, Martin KarplusAbstract:An adaptive Umbrella Sampling molecular dynamics algorithm based on the potential energy is introduced to reduce the simulation time required for deriving equilibrium properties of molecular systems. The potential energy, in contrast to the commonly used Umbrella potentials, is of particular interest for complex systems because it does not depend on assumptions about the geometry nor on a knowledge of the important conformations and transition states that are involved in the equilibration. The method is illustrated by applying it to the threonine dipeptide and to met-Enkephalin. For the threonine dipeptide, potentials of mean force for all dihedral angles of the system are derived from a single 10 ns run. The accuracy of the potentials is confirmed by comparison with previous results. Met-Enkephalin is found to sample several different conformations at 300 K. Three representative structures are used to cluster the dominant conformations. Equilibrium distributions of dihedral angles and the distance betwee...
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multidimensional adaptive Umbrella Sampling applications to main chain and side chain peptide conformations
Journal of Computational Chemistry, 1997Co-Authors: Christian Bartels, Martin KarplusAbstract:A new adaptive Umbrella Sampling technique for molecular dynamics simulations is described. The high efficiency of the technique renders multidimensional adaptive Umbrella Sampling possible and thereby enables uniform Sampling of the conformational space spanned by several degrees of freedom. The efficiency is achieved by using the weighted histogram analysis method to combine the results from different simulations, by a suitable extrapolation scheme to define the Umbrella potential for regions that have not been sampled, and by a criterion to identify simulations during which the system was not in equilibrium. The technique is applied to two test systems, the alanine dipeptide and the threonine dipeptide, to sample the configurational space spanned by one or two dihedral angles. The Umbrella potentials applied at the end of each adaptive Umbrella Sampling run are equal to the negative of the corresponding potentials of mean force. The trajectories obtained in the simulations can be used to calculate dynamical variables that are of interest. An example is the distribution of the distance between the HN and the H b proton that can be important for the interpretation of NMR experiments. Factors influencing the accuracy of the calculated quantities are discussed. Q 1997 John Wiley & Sons, Inc. J Comput Chem 18: 1450)1462, 1997
Benoit Roux - One of the best experts on this subject based on the ideXlab platform.
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leveraging the information from markov state models to improve the convergence of Umbrella Sampling simulations
Journal of Physical Chemistry B, 2016Co-Authors: Donghyuk Suh, Benoit Roux, Christophe ChipotAbstract:Umbrella Sampling (US) simulation is a highly effective method for Sampling the conformations of a complex system within a small subspace of predefined coordinates. In a typical US stratification strategy, biasing “window” potentials spanning the subspace of interest are introduced to narrow down the range of accessible conformations and accelerate the Sampling. The speed of convergence in each biased window simulation may, however, differ. For example, windows that coincide with a large energetic barrier along a coordinate that is orthogonal to the predefined subspace are often plagued by slow relaxation timescales. Here, we design a method that can quantitatively detect this type of issue and gain further insight into the origin of the slow relaxation timescale. Once the problematic windows affected by slow convergence are identified, additional simulations limited to only these windows can be carried out, thereby reducing the overall computational effort. Several possible approaches aimed at performing...
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efficient determination of free energy landscapes in multiple dimensions from biased Umbrella Sampling simulations using linear regression
Journal of Chemical Theory and Computation, 2015Co-Authors: Yilin Meng, Benoit RouxAbstract:The weighted histogram analysis method (WHAM) is a standard protocol for postprocessing the information from biased Umbrella Sampling simulations to construct the potential of mean force with respect to a set of order parameters. By virtue of the WHAM equations, the unbiased density of state is determined by satisfying a self-consistent condition through an iterative procedure. While the method works very effectively when the number of order parameters is small, its computational cost grows rapidly in higher dimension. Here, we present a simple and efficient alternative strategy, which avoids solving the self-consistent WHAM equations iteratively. An efficient multivariate linear regression framework is utilized to link the biased probability densities of individual Umbrella windows and yield an unbiased global free energy landscape in the space of order parameters. It is demonstrated with practical examples that free energy landscapes that are comparable in accuracy to WHAM can be generated at a small fraction of the cost.
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self learning adaptive Umbrella Sampling method for the determination of free energy landscapes in multiple dimensions
Journal of Chemical Theory and Computation, 2013Co-Authors: Wojciech Wojtasniziurski, Benoit Roux, Yilin Meng, Simon BernecheAbstract:The potential of mean force describing conformational changes of biomolecules is a central quantity for understanding the function of biomolecular systems. Calculating an energy landscape of a process that depends on three or more reaction coordinates requires extensive computational power, making some multidimensional calculations practically impossible. Here, we present an efficient automatized Umbrella Sampling strategy for calculating a multidimensional potential of mean force. The method progressively learns by itself, through a feedback mechanism, which regions of a multidimensional space are worth exploring and automatically generates a set of Umbrella Sampling windows that is adapted to the system. The self-learning adaptive Umbrella Sampling method is first explained with illustrative examples based on simplified reduced model systems and then applied to two nontrivial situations: the conformational equilibrium of the pentapeptide Met-enkephalin in solution and ion permeation in the KcsA potassiu...
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calculation of free energy landscape in multi dimensions with hamiltonian exchange Umbrella Sampling on petascale supercomputer
Journal of Chemical Theory and Computation, 2012Co-Authors: Wei Jiang, Luca Maragliano, Benoit RouxAbstract:An extremely scalable computational strategy is described for calculations of the potential of mean force (PMF) in multidimensions on massively distributed supercomputers. The approach involves coupling thousands of Umbrella Sampling (US) simulation windows distributed to cover the space of order parameters with a Hamiltonian molecular dynamics replica-exchange (H-REMD) algorithm to enhance the Sampling of each simulation. In the present application, US/H-REMD is carried out in a two-dimensional (2D) space and exchanges are attempted alternatively along the two axes corresponding to the two order parameters. The US/H-REMD strategy is implemented on the basis of parallel/parallel multiple copy protocol at the MPI level, and therefore can fully exploit computing power of large-scale supercomputers. Here the novel technique is illustrated using the leadership supercomputer IBM Blue Gene/P with an application to a typical biomolecular calculation of general interest, namely the binding of calcium ions to the ...
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extension to the weighted histogram analysis method combining Umbrella Sampling with free energy calculations
Computer Physics Communications, 2001Co-Authors: Marc Souaille, Benoit RouxAbstract:The Weighted Histogram Analysis Method (WHAM) of Kumar et al. (J. Comput. Chem. 13 (1992) 1011), is used to combine free energy perturbations with Umbrella Sampling calculations. The formulation is general and allows optimal calculation of the free energies from a set of molecular dynamics simulations generated in the presence of arbitrary biasing Umbrella Sampling window potentials. The method yields the free energy associated with a given simulation as well as the probability distribution of the molecular system configurations by extracting the information contained in all the biased simulations (the windows) in an optimal way. The method presents some advantages compared to the standard free energy perturbation (FEP) and thermodynamic integration (TI) methods, because the window potential can be used for restricting the conformational space to specific regions during free energy calculations.
Steffen Lindert - One of the best experts on this subject based on the ideXlab platform.
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mechanism of cardiac troponin c calcium sensitivity modulation by small molecules illuminated by Umbrella Sampling simulations
Journal of Chemical Information and Modeling, 2019Co-Authors: Jacob D Bowman, William H Coldren, Steffen LindertAbstract:Cardiac troponin C (cTnC) binds intracellular calcium and subsequently cardiac troponin I (cTnI), initiating cardiac muscle contraction. Due to its role in contraction, cTnC has been a therapeutic target in the search for small molecules to treat conditions that interfere with normal muscle contraction like the heritable cardiomyopathies. Structural studies have shown the binding location of small molecules such as bepridil, dfbp-o, 3-methyldiphenylamine (DPA), and W7 to be a hydrophobic pocket in the regulatory domain of cTnC (cNTnC) but have not shown the influence of these small molecules on the energetics of opening this domain. Here we describe an application of an Umbrella Sampling method used to elucidate the impact these calcium sensitivity modulators have on the free energy of cNTnC hydrophobic patch opening. We found that all these molecules lowered the free energy of opening in the absence of the cTnI, with bepridil facilitating the least endergonic transformation. In the presence of cTnI, howe...
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mechanism of cardiac troponin c calcium sensitivity modulation by small molecules illuminated by Umbrella Sampling simulations
Journal of Chemical Information and Modeling, 2019Co-Authors: Jacob D Bowman, William H Coldren, Steffen LindertAbstract:Cardiac troponin C (cTnC) binds intracellular calcium and subsequently cardiac troponin I (cTnI), initiating cardiac muscle contraction. Due to its role in contraction, cTnC has been a therapeutic target in the search for small molecules to treat conditions that interfere with normal muscle contraction like the heritable cardiomyopathies. Structural studies have shown the binding location of small molecules such as bepridil, dfbp-o, 3-methyldiphenylamine (DPA), and W7 to be a hydrophobic pocket in the regulatory domain of cTnC (cNTnC) but have not shown the influence of these small molecules on the energetics of opening this domain. Here we describe an application of an Umbrella Sampling method used to elucidate the impact these calcium sensitivity modulators have on the free energy of cNTnC hydrophobic patch opening. We found that all these molecules lowered the free energy of opening in the absence of the cTnI, with bepridil facilitating the least endergonic transformation. In the presence of cTnI, however, we saw a stabilization of the open configuration due to DPA and dfbp-o binding, and a destabilization of the open configuration imparted by bepridil and W7. Predicted poor binding molecule NSC34337 left the hydrophobic patch in under 3 ns in conventional MD simulations suggesting that only hydrophobic patch binders stabilized the open conformation. In conclusion, this study presents a novel approach to study the impact of small molecules on hydrophobic patch opening through Umbrella Sampling, and it proposes mechanisms for calcium sensitivity modulation.
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molecular dynamics and Umbrella Sampling simulations elucidate differences in troponin c isoform and mutant hydrophobic patch exposure
Journal of Physical Chemistry B, 2018Co-Authors: Jacob D Bowman, Steffen LindertAbstract:Troponin C (TnC) facilitates muscle contraction through calcium-binding within its N-terminal region (NTnC). As previously observed using molecular dynamics (MD) simulations, this calcium-binding event leads to an increase in the dynamics of helices lining a hydrophobic patch on TnC. Simulation times of multiple microseconds were required to even see a partial opening of the hydrophobic patch, limiting the ability to thoroughly and quantitatively investigate these rare events. Here we describe the application of Umbrella Sampling to probe the TnC hydrophobic patch opening in a more targeted and quantitative fashion. Umbrella Sampling was utilized to investigate the differences in the free energy of opening between cardiac (cTnC) and fast skeletal TnC (sTnC). We found that, in agreement with previous reports, holo (calcium-bound) sTnC had a lower free energy of opening compared with holo cTnC. Additionally, differences in the free energy of opening of hypertrophic (HCM) and dilated cardiomyopathy (DCM) cTn...
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molecular dynamics and Umbrella Sampling simulations elucidate differences in troponin c isoform and mutant hydrophobic patch exposure
Journal of Physical Chemistry B, 2018Co-Authors: Jacob D Bowman, Steffen LindertAbstract:Troponin C (TnC) facilitates muscle contraction through calcium-binding within its N-terminal region (NTnC). As previously observed using molecular dynamics (MD) simulations, this calcium-binding event leads to an increase in the dynamics of helices lining a hydrophobic patch on TnC. Simulation times of multiple microseconds were required to even see a partial opening of the hydrophobic patch, limiting the ability to thoroughly and quantitatively investigate these rare events. Here we describe the application of Umbrella Sampling to probe the TnC hydrophobic patch opening in a more targeted and quantitative fashion. Umbrella Sampling was utilized to investigate the differences in the free energy of opening between cardiac (cTnC) and fast skeletal TnC (sTnC). We found that, in agreement with previous reports, holo (calcium-bound) sTnC had a lower free energy of opening compared with holo cTnC. Additionally, differences in the free energy of opening of hypertrophic (HCM) and dilated cardiomyopathy (DCM) cTnC systems were investigated. MD simulations and Umbrella Sampling revealed a lower free energy of opening for the HCM mutations A8V and A31S, as well as the calcium-sensitizing mutation L48Q. The DCM mutations, Y5H, Q50R, and E59D/D75Y, all exhibited a higher free energy of opening. An Umbrella Sampling simulation of cTnI-bound holo cTnC exhibited the lowest free energy in the open configuration, in agreement with experimental data. In conclusion, this study presents a novel and successful protocol for applying Umbrella Sampling simulations to quantitatively study the molecular basis of muscle contraction and proposes a mechanism by which HCM and DCM-associated mutations influence contraction.
Jacob D Bowman - One of the best experts on this subject based on the ideXlab platform.
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mechanism of cardiac troponin c calcium sensitivity modulation by small molecules illuminated by Umbrella Sampling simulations
Journal of Chemical Information and Modeling, 2019Co-Authors: Jacob D Bowman, William H Coldren, Steffen LindertAbstract:Cardiac troponin C (cTnC) binds intracellular calcium and subsequently cardiac troponin I (cTnI), initiating cardiac muscle contraction. Due to its role in contraction, cTnC has been a therapeutic target in the search for small molecules to treat conditions that interfere with normal muscle contraction like the heritable cardiomyopathies. Structural studies have shown the binding location of small molecules such as bepridil, dfbp-o, 3-methyldiphenylamine (DPA), and W7 to be a hydrophobic pocket in the regulatory domain of cTnC (cNTnC) but have not shown the influence of these small molecules on the energetics of opening this domain. Here we describe an application of an Umbrella Sampling method used to elucidate the impact these calcium sensitivity modulators have on the free energy of cNTnC hydrophobic patch opening. We found that all these molecules lowered the free energy of opening in the absence of the cTnI, with bepridil facilitating the least endergonic transformation. In the presence of cTnI, howe...
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mechanism of cardiac troponin c calcium sensitivity modulation by small molecules illuminated by Umbrella Sampling simulations
Journal of Chemical Information and Modeling, 2019Co-Authors: Jacob D Bowman, William H Coldren, Steffen LindertAbstract:Cardiac troponin C (cTnC) binds intracellular calcium and subsequently cardiac troponin I (cTnI), initiating cardiac muscle contraction. Due to its role in contraction, cTnC has been a therapeutic target in the search for small molecules to treat conditions that interfere with normal muscle contraction like the heritable cardiomyopathies. Structural studies have shown the binding location of small molecules such as bepridil, dfbp-o, 3-methyldiphenylamine (DPA), and W7 to be a hydrophobic pocket in the regulatory domain of cTnC (cNTnC) but have not shown the influence of these small molecules on the energetics of opening this domain. Here we describe an application of an Umbrella Sampling method used to elucidate the impact these calcium sensitivity modulators have on the free energy of cNTnC hydrophobic patch opening. We found that all these molecules lowered the free energy of opening in the absence of the cTnI, with bepridil facilitating the least endergonic transformation. In the presence of cTnI, however, we saw a stabilization of the open configuration due to DPA and dfbp-o binding, and a destabilization of the open configuration imparted by bepridil and W7. Predicted poor binding molecule NSC34337 left the hydrophobic patch in under 3 ns in conventional MD simulations suggesting that only hydrophobic patch binders stabilized the open conformation. In conclusion, this study presents a novel approach to study the impact of small molecules on hydrophobic patch opening through Umbrella Sampling, and it proposes mechanisms for calcium sensitivity modulation.
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molecular dynamics and Umbrella Sampling simulations elucidate differences in troponin c isoform and mutant hydrophobic patch exposure
Journal of Physical Chemistry B, 2018Co-Authors: Jacob D Bowman, Steffen LindertAbstract:Troponin C (TnC) facilitates muscle contraction through calcium-binding within its N-terminal region (NTnC). As previously observed using molecular dynamics (MD) simulations, this calcium-binding event leads to an increase in the dynamics of helices lining a hydrophobic patch on TnC. Simulation times of multiple microseconds were required to even see a partial opening of the hydrophobic patch, limiting the ability to thoroughly and quantitatively investigate these rare events. Here we describe the application of Umbrella Sampling to probe the TnC hydrophobic patch opening in a more targeted and quantitative fashion. Umbrella Sampling was utilized to investigate the differences in the free energy of opening between cardiac (cTnC) and fast skeletal TnC (sTnC). We found that, in agreement with previous reports, holo (calcium-bound) sTnC had a lower free energy of opening compared with holo cTnC. Additionally, differences in the free energy of opening of hypertrophic (HCM) and dilated cardiomyopathy (DCM) cTn...
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molecular dynamics and Umbrella Sampling simulations elucidate differences in troponin c isoform and mutant hydrophobic patch exposure
Journal of Physical Chemistry B, 2018Co-Authors: Jacob D Bowman, Steffen LindertAbstract:Troponin C (TnC) facilitates muscle contraction through calcium-binding within its N-terminal region (NTnC). As previously observed using molecular dynamics (MD) simulations, this calcium-binding event leads to an increase in the dynamics of helices lining a hydrophobic patch on TnC. Simulation times of multiple microseconds were required to even see a partial opening of the hydrophobic patch, limiting the ability to thoroughly and quantitatively investigate these rare events. Here we describe the application of Umbrella Sampling to probe the TnC hydrophobic patch opening in a more targeted and quantitative fashion. Umbrella Sampling was utilized to investigate the differences in the free energy of opening between cardiac (cTnC) and fast skeletal TnC (sTnC). We found that, in agreement with previous reports, holo (calcium-bound) sTnC had a lower free energy of opening compared with holo cTnC. Additionally, differences in the free energy of opening of hypertrophic (HCM) and dilated cardiomyopathy (DCM) cTnC systems were investigated. MD simulations and Umbrella Sampling revealed a lower free energy of opening for the HCM mutations A8V and A31S, as well as the calcium-sensitizing mutation L48Q. The DCM mutations, Y5H, Q50R, and E59D/D75Y, all exhibited a higher free energy of opening. An Umbrella Sampling simulation of cTnI-bound holo cTnC exhibited the lowest free energy in the open configuration, in agreement with experimental data. In conclusion, this study presents a novel and successful protocol for applying Umbrella Sampling simulations to quantitatively study the molecular basis of muscle contraction and proposes a mechanism by which HCM and DCM-associated mutations influence contraction.
