Solution structure of cardiotoxin V from Naja naja atra

Singhal, Arun; Chien, Kun-Yi; Wu, Wenwen; Rule, Gordon S.

doi:10.1021/bi00082a026

Cited by 46 publications

(52 citation statements)

References 34 publications

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“…86 The input structures of all test systems were generated from the CHARMM22 topology files 87 using the CHARMMing server. 88 The N-termini and C-termini of all test systems are capped with the neutral acetyl and N -methyl groups, respectively.…”

Section: Methodsmentioning

confidence: 99%

Constant pH Molecular Dynamics in Explicit Solvent with Enveloping Distribution Sampling and Hamiltonian Exchange

Lee

Miller

Damjanović

et al. 2014

J. Chem. Theory Comput.

119

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We present a new computational approach for constant pH simulations in explicit solvent based on the combination of the enveloping distribution sampling (EDS) and Hamiltonian replica exchange (HREX) methods. Unlike constant pH methods based on variable and continuous charge models, our method is based on discrete protonation states. EDS generates a hybrid Hamiltonian of different protonation states. A smoothness parameter s is used to control the heights of energy barriers of the hybrid-state energy landscape. A small s value facilitates state transitions by lowering energy barriers. Replica exchange between EDS potentials with different s values allows us to readily obtain a thermodynamically accurate ensemble of multiple protonation states with frequent state transitions. The analysis is performed with an ensemble obtained from an EDS Hamiltonian without smoothing, s = ∞, which strictly follows the minimum energy surface of the end states. The accuracy and efficiency of this method is tested on aspartic acid, lysine, and glutamic acid, which have two protonation states, a histidine with three states, a four-residue peptide with four states, and snake cardiotoxin with eight states. The pKa values estimated with the EDS-HREX method agree well with the experimental pKa values. The mean absolute errors of small benchmark systems range from 0.03 to 0.17 pKa units, and those of three titratable groups of snake cardiotoxin range from 0.2 to 1.6 pKa units. This study demonstrates that EDS-HREX is a potent theoretical framework, which gives the correct description of multiple protonation states and good calculated pKa values.

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Section: Methodsmentioning

confidence: 99%

Constant pH Molecular Dynamics in Explicit Solvent with Enveloping Distribution Sampling and Hamiltonian Exchange

Lee

Miller

Damjanović

et al. 2014

J. Chem. Theory Comput.

119

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show abstract

“…Five systems were used to assess the performance of the 2D exchange method: aspartic acid, glutamic acid, and lysine monomers, a four residue peptide with sequence KAAE, and snake cardiotoxin V from Naja naja atra (CTX A5, Protein Data Bank (PDB) ID: 1CVO). 70 The initial structures of all test systems were generated by the CHARMMing server 71 with the CHARMM22 parameters. 58 The N-and C-termini of all systems were capped with the neutral acetyl and N-methyl groups.…”

Section: Two-dimensional Replica Exchangementioning

confidence: 99%

Enhancing Constant-pH Simulation in Explicit Solvent with a Two-Dimensional Replica Exchange Method

Lee

Miller

Damjanović

et al. 2015

J. Chem. Theory Comput.

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We present a new method for enhanced sampling for constant-pH simulations in explicit water based on a two-dimensional (2D) replica exchange scheme. The new method is a significant extension of our previously developed constant-pH simulation method, which is based on enveloping distribution sampling (EDS) coupled with a one-dimensional (1D) Hamiltonian exchange method (HREM). EDS constructs a hybrid Hamiltonian from multiple discrete end state Hamiltonians that, in this case, represent different protonation states of the system. The ruggedness and heights of the hybrid Hamiltonian's energy barriers can be tuned by the smoothness parameter. Within the context of the 1D EDS-HREM method, exchanges are performed between replicas with different smoothness parameters, allowing frequent protonation-state transitions and sampling of conformations that are favored by the end-state Hamiltonians. In this work, the 1D method is extended to 2D with an additional dimension, external pH. Within the context of the 2D method (2D EDS-HREM), exchanges are performed on a lattice of Hamiltonians with different pH conditions and smoothness parameters. We demonstrate that both the 1D and 2D methods exactly reproduce the thermodynamic properties of the semigrand canonical (SGC) ensemble of a system at a given pH. We have tested our new 2D method on aspartic acid, glutamic acid, lysine, a four residue peptide (sequence KAAE), and snake cardiotoxin. In all cases, the 2D method converges faster and without loss of precision; the only limitation is a loss of flexibility in how CPU time is employed. The results for snake cardiotoxin demonstrate that the 2D method enhances protonation-state transitions, samples a wider conformational space with the same amount of computational resources, and converges significantly faster overall than the original 1D method.

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“…10,[12][13][14]. The toxins adopt an all ␤-sheet three-finger loop structure held together by four disulfide bonds (for review, see Ref.…”

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confidence: 99%

Heparin and Heparan Sulfate Bind to Snake Cardiotoxin

Patel

Vyas

et al. 1997

Journal of Biological Chemistry

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Cardiotoxins (CTXs) from cobra venom show cytotoxicity toward several cell types. They cause systolic heart arrest and severe tissue necrosis. Their interaction with phospholipids is established but by itself fails to explain the specificity of these toxins; other component(s) of membrane must, therefore, intervene to direct them toward their target. We herein show, for the first time, that sulfated glycosaminoglycans, heparin, heparan sulfate (HS), chondroitin sulfate (CS), and dermatan sulfate (DS), interact with CTX A3, a major component of Taiwan cobra venom, by use of affinity chromatography, circular dichroism, absorbance, and fluorescence intensity and anisotropy measurements. The relative strength of binding, determined by the NaCl concentration required to dissociate the CTX-glycosaminoglycan complex, varied as follows: heparin > DS > CS > HS. In physiological buffer (8 mM Na 2 HPO 4 , 2.7 mM KCl, 1.8 mM KH 2 PO 4 , 138 mM NaCl, pH 7.4), however, only heparin and HS bound to CTX, with respective dissociation constants of 1.4 and 16 M, while CS and DS failed to exhibit well defined binding behavior, as indicated by fluorescence measurements. We estimate that CTX makes 3-4 ionic contacts with heparin based on a salt-dependent binding study and that ϳ40% of binding free energy is derived from purely electrostatic interactions under physiological conditions. Sulfated pentasaccharide may be sufficient to bind to CTX. We also found that heparin accentuates the penetration of CTX into phospholipid membranes as analyzed by Langmuir monolayer measurement. In view of these results we propose that heparin-like moieties of the cell surface may modulate the action of CTX.

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Solution structure of cardiotoxin V from Naja naja atra

Cited by 46 publications

References 34 publications

Constant pH Molecular Dynamics in Explicit Solvent with Enveloping Distribution Sampling and Hamiltonian Exchange

Constant pH Molecular Dynamics in Explicit Solvent with Enveloping Distribution Sampling and Hamiltonian Exchange

Enhancing Constant-pH Simulation in Explicit Solvent with a Two-Dimensional Replica Exchange Method

Heparin and Heparan Sulfate Bind to Snake Cardiotoxin

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