Molecular Dynamics Simulation of Folding of a Short Helical Toxin Peptide

Tsai, Yi Len; Chen, Hwung Wen; Lin, Topp; Wang, Weizhou; Sun, Yu

doi:10.1142/s0219633607002964

Cited by 3 publications

(3 citation statements)

References 31 publications

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“…Experimentally, SS bonds can be removed with reducing agents such as β-mercaptoethanol and dithiothreitol, and their formation is prevented by inhibitors such as iodoacetamide or iodoacetic acid. − SS bonds play different roles in maintaining structure, stability, and functionality. The effect of SS bonds on the structure and dynamics of different proteins has been a subject of interest experimentally − and computationally. − Some of the consequences of removing disulfide bonds include a decrease in the stability of the unfolded state, changes in the formation of correct SS bond pairs, and a localized destabilization and decrease in activity …”

Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of Human Serum Albumin and Role of Disulfide Bonds

Castellanos

Colina

2013

J. Phys. Chem. B

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Atomistic molecular dynamics simulations of human serum albumin in the presence and absence of disulfide bonds are presented. Simulations of 70 ns duration provide information on the relevance of disulfide bonds in the dynamics and structural conformation of HSA. Significant conformational changes are observed in the absence of disulfide bonds after 35 ns that could impact the functionality and stability of the protein. Changes in the secondary structure, hydrogen bonds, B factors, and cross-correlations reveal which disulfide bonds are important for keeping the secondary and tertiary structure and dynamics of the protein (e.g., Cys168-Cys177, Cys278-Cys289) and which have little effect on the local structure and dynamics (e.g., Cys200-Cys246, Cys461-Cys477). Removing all disulfide bonds in the protein appears to be a practical prescreening tool for identifying disulfide bonds relevant to structure and dynamics. In the absence of disulfide bonds, certain hydrogen bonds and correlated motions vanish, affecting the structure of neighboring residues. The structure of the primary binding sites of HSA is partially affected when disulfide bonds are removed. For the native structure, simulations clearly reveal the conformational changes that allow the only free cysteine to be exposed on the protein surface to form intermolecular disulfide bonds; this information could not be resolved from the static crystal structure alone. The absence of specific disulfide bonds could lead to partially unfolded structures; such structures are known to be prone to protein aggregation. Removing disulfide bonds could have similar consequences in other proteins of interest, such as immunoglobulin G.

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Section: Introductionmentioning

confidence: 99%

Molecular Dynamics Simulations of Human Serum Albumin and Role of Disulfide Bonds

Castellanos

Colina

2013

J. Phys. Chem. B

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“…Disulfide bonds (bridges) or SS bonds are covalent bonds formed from two thiol groups [75,76]. The effect of SS bonds on the protein structural stability, dynamics, correlated motion, and flexibility of local residues has been investigated experimentally [77][78][79][80] and computationally [81][82][83][84][85][86][87]. Three necessary conditions were formulated [88] for cycteins pairs to be involved in SS bonds: a bond length of 2.050.3Å, an angle between the sulfur atoms and -carbon atom of 103 0 , and an orientation of the two -carbon atoms corresponding to a rotation of 90° about the SS bonds.…”

Section: Accepted Manuscriptmentioning

confidence: 99%

The effect of water dynamics on conformation changes of albumin in pre-denaturation state: photon correlation spectroscopy and simulation

Atamas

Bardik

Банникова

et al. 2017

Journal of Molecular Liquids

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Water is essential for protein three-dimensional structure, conformational dynamics, and activity. Human serum albumin (HSA) is one of major blood plasma proteins, and its functioning is fundamentally determined by the dynamics of surrounding water. The goal of this study is to link the conformational dynamics of albumin to the thermal motions in water taking place in the physiological temperature range. We report the results of photon correlation spectroscopy and molecular dynamics simulations of HSA in aqueous solution. The experimental data processing produced the temperature dependence of the HSA hydrodynamic radius and its zeta potential. Molecular dynamics reproduced the results of experiments and revealed changes in the secondary structure caused by the destruction of hydrogen bonds in the macromolecule's globule.

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“…For the majority of successfully folded proteins there are significant discrepancies between simulated and experimental folding times [5][6][7]. This is taking into account that only the results when the trajectories approach the folded conformations sufficiently close are published.…”

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confidence: 99%

Why Are MD Simulated Protein Folding Times Wrong?

Nerukh

2010

Advances in Experimental Medicine and Biology

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The question of significant deviations of protein folding times simulated using molecular dynamics from experimental values is investigated. It is shown that, in the framework of Markov State Model describing the conformational dynamics of peptides and proteins, the folding time is very sensitive to the simulation model parameters, such as forcefield and temperature. Using two peptides as examples we show that the deviations in the folding times can reach an order of magnitude for modest variations of the molecular model. We, therefore, conclude that the folding rate values obtained in molecular dynamics simulations have to be treated with care.Modern computational power is enough to simulate small proteins up to the times when they fold into their native conformations [1][2][3][4]. This is a remarkable achievement because phenomenological, relatively simple interatomic interactions built into the model lead to the molecular structures that essentially coincide with the crystallographically determined native conformations.In contrast to the structure of proteins, the results on folding times are not as optimistic. For the majority of successfully folded proteins there are significant discrepancies between simulated and experimental folding times [5][6][7]. This is taking into account that only the results when the trajectories approach the folded conformations sufficiently close are published. In few cases even complete failures to reach the folded state in silico in simulations significantly exceeding the experimental folding times are reported [8]. Indeed it is well known in the modelling community how difficult it is no fold a protein ab initio, that is without introducing any information on the intermediates.By analysing the MD trajectories of peptides in explicit water we suggest an explanation for these discrepancies. We show that the folding rates are very sensitive to the details of the simulation model. The sensitivity is so high that the obtained values of folding times are meaningless and can not be compared between each other and with the experiment.We use the Markov State Model (MSM) [9-12] to describe the folding process. The configurational states are defined by clustering the MD simulated trajectories. This is done by analysing the Ramachandran plots of the residues of the peptide, Fig. 1. Each Ramachandran plot is clustered independently and the molecule's configurations are defined by the cluster indices from each plot. Not all possible combinations of index values are realised in the trajectory. For example, for the peptide from Fig. 1 the conformation B 1 C 2 was very scarcely populated and was, therefore, joined with A 1 C 2 into one conformation, thus resulting in 5 total configurations of the molecule.In the MSM framework the model is described by a state vector v, which holds probabilities of all the configurations at a given moment of time, and a transition matrix T . The total probability of the state vector has to sum to 100% since the peptide has to be in some configuration at any tim...

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Molecular Dynamics Simulation of Folding of a Short Helical Toxin Peptide

Cited by 3 publications

References 31 publications

Molecular Dynamics Simulations of Human Serum Albumin and Role of Disulfide Bonds

Molecular Dynamics Simulations of Human Serum Albumin and Role of Disulfide Bonds

The effect of water dynamics on conformation changes of albumin in pre-denaturation state: photon correlation spectroscopy and simulation

Why Are MD Simulated Protein Folding Times Wrong?

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