Effect of High Exogenous Electric Pulses on Protein Conformation: Myoglobin as a Case Study

Marracino, Paolo; Apollonio, Francesca; Liberti, Micaela; D’Inzeo, G.; Amadei, Andrea

doi:10.1021/jp309857b

Cited by 89 publications

(86 citation statements)

References 56 publications

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“…To note that the figure confirms how this holds true for both the protein and the water phases, since even water molecules near charged residues act very differently from the bulk water, and they establish peculiar hydrogen bonds networks with the different residues [17,40,42].…”

Section: Resultssupporting

confidence: 64%

“…13.5 (upper part), showing an enhancement of the potential gradient due to the field that possibly leads to the unfolding transitions as the one observed in [40] for higher intensity fields of 10 9 V/m.…”

Section: Resultsmentioning

confidence: 76%

“…Trajectory obtained in [40] has been used as the reference one, i.e. the trajectory from which the physiological properties of myoglobin can be evaluated and, more important, whereby, data obtained in presence of the electric field perturbations can be compared.…”

Section: B Simulated System and The Analysis Tool Implemented For Elmentioning

confidence: 99%

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Evaluation of Protein Electrostatic Potential from Molecular Dynamics Simulations in the Presence of Exogenous Electric Fields: The Case Study of Myoglobin

Marracino

Casciola

Liberti

et al. 2014

Computational Electrostatics for Biological Applications

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When studying proteins in solution it is apparent that electrostatic interactions play a role in folding, conformational stability, and other chemicalphysical properties. Electrostatics considers the evaluation of the static electrical field that is formed between charged species once a rearrangement of their charge distributions has occurred due to the influence of each other and their local environment. A powerful tool used to follow the many interactions among the polar and/or charged residues is computer simulations, which can provide atomic-scale information on energetic and dynamic contributions of the bio-molecular structure. Here we use molecular dynamics (MD) simulations to map on a three-dimensional space the electrostatic interactions within the protein itself and of the protein with its aqueous environment. The method has been first tested on a simulation domain of water molecules and then applied to the myoglobin-water system. The presence of intense electric fields has also been considered and some representative results are discussed. IntroductionThe electrostatic interactions between charged atoms in natural proteins play a central role in specifying protein topology, modulating stability of the molecule, and allowing for the important catalytic properties of enzymes. Such kind of interactions are at the basis of molecular characterization; when studying biomolecules it is becoming increasingly evident that electrostatic interactions play a role in folding, conformational stability, enzyme activity, and binding energies as well as in

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Section: Resultssupporting

confidence: 64%

Section: Resultsmentioning

confidence: 76%

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Evaluation of Protein Electrostatic Potential from Molecular Dynamics Simulations in the Presence of Exogenous Electric Fields: The Case Study of Myoglobin

Marracino

Casciola

Liberti

et al. 2014

Computational Electrostatics for Biological Applications

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“…Despite its importance, the mechanism of folding/unfolding of HoloMb has not been studied in detail, except from a very recent study of the electric-field induced unfolding of HoloMb, which produced remarkable stretched intermediates with only 13–20% helicity [52]. The holoMb unfolding mechanism is central to understanding the protein in vivo [53] and must differ from that of the apoprotein due to the differences in helix structure and the role of heme.…”

Section: Introductionmentioning

confidence: 99%

Unfolding Simulations of Holomyoglobin from Four Mammals: Identification of Intermediates and β-Sheet Formation from Partially Unfolded States

Dasmeh

Kepp

2013

PLoS ONE

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Myoglobin (Mb) is a centrally important, widely studied mammalian protein. While much work has investigated multi-step unfolding of apoMb using acid or denaturant, holomyoglobin unfolding is poorly understood despite its biological relevance. We present here the first systematic unfolding simulations of holoMb and the first comparative study of unfolding of protein orthologs from different species (sperm whale, pig, horse, and harbor seal). We also provide new interpretations of experimental mean molecular ellipticities of myoglobin intermediates, notably correcting for random coil and number of helices in intermediates. The simulated holoproteins at 310 K displayed structures and dynamics in agreement with crystal structures (R g ∼1.48–1.51 nm, helicity ∼75%). At 400 K, heme was not lost, but some helix loss was observed in pig and horse, suggesting that these helices are less stable in terrestrial species. At 500 K, heme was lost within 1.0–3.7 ns. All four proteins displayed exponentially decaying helix structure within 20 ns. The C- and F-helices were lost quickly in all cases. Heme delayed helix loss, and sperm whale myoglobin exhibited highest retention of heme and D/E helices. Persistence of conformation (RMSD), secondary structure, and ellipticity between 2–11 ns was interpreted as intermediates of holoMb unfolding in all four species. The intermediates resemble those of apoMb notably in A and H helices, but differ substantially in the D-, E- and F-helices, which interact with heme. The identified mechanisms cast light on the role of metal/cofactor in poorly understood holoMb unfolding. We also observed β-sheet formation of several myoglobins at 500 K as seen experimentally, occurring after disruption of helices to a partially unfolded, globally disordered state; heme reduced this tendency and sperm-whale did not display any sheet propensity during the simulations.

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“…A very large number of distinct conformations exist for the polypeptide chain of which a protein molecule is composed. The protein spends most of its time in the native conformation, which spans only an infinitesimal fraction of the entire configuration space [10]. The general perception has been that the protein folding problem is a grand challenge that will require many supercomputer years to solve.…”

Section: Introductionmentioning

confidence: 99%

Protein Folding and Misfolding: A Perspective from Theory

TA¹

2015

J Glycomics Lipidomics

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IntroductionIn appropriate physiological milieu proteins spontaneously fold into their functional three-dimensional structures. The amino acid sequences of functional proteins contain all the information necessary to specify the folds [1,2]. The manner in which a newly synthesized chain of amino acids transforms itself into a perfectly folded protein depends both on the intrinsic properties of the amino-acid sequence and on multiple contributing influences from the crowded cellular milieu. The wide variety of highly specific structures that result from protein folding and that bring key functional groups into close proximity has enabled living systems to develop astonishing diversity and selectivity in their underlying chemical processes. In addition to generating biological activity, we now know that folding is coupled to many other biological processes, including the trafficking of molecules to specific cellular locations and the regulation of cellular growth and differentiation [3,4].Add to it, correctly folded proteins have long-term stability in crowded biological environments and are able to interact selectively with their natural partners. It is therefore not surprising that the failure of proteins to fold correctly is the origin of a wide variety of pathological conditions [5]. Some concepts, such as energy landscape, Gibbs energy landscape and co-operativity frequently used in the theory of protein folding are examined exactly in one-dimensional systems. It is shown that much of the confusion that exists regarding these, and other concepts arise from the misinterpretation of Anfinsen's thermodynamic hypothesis [6].Moreover, proteins are involved in virtually every biological process and their functions range from catalysis of chemical reactions to maintenance of the electrochemical potential across cell membranes. The molecular conformation of proteins is sensitive to the nature of the aqueous environment [7]. They are synthesized on ribosomes as linear chains of amino acids in a specific order from information encoded within the cellular DNA. To function, it is necessary for these chains to fold into the unique native three dimensional structures that are characteristic for each protein (Figure 1). This involves a complex molecular recognition phenomenon that depends on the cooperative action of many relatively weak non-bonding interactions. As the number of possible conformations for a polypeptide chain is astronomically large, a systematic search for the native (lowest energy) structure would require an almost infinite length of time. Recently, significant progress has been made towards solving this paradox and understanding the mechanism of folding. This has come about through advances in experimental strategies for following the folding reactions of proteins in the laboratory with biophysical techniques, and through progress in theoretical approaches that simulate the folding process with simplified models [8,9].Protein folding is a problem of great importance in both life sciences and biotechnolog...

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Effect of High Exogenous Electric Pulses on Protein Conformation: Myoglobin as a Case Study

Cited by 89 publications

References 56 publications

Evaluation of Protein Electrostatic Potential from Molecular Dynamics Simulations in the Presence of Exogenous Electric Fields: The Case Study of Myoglobin

Evaluation of Protein Electrostatic Potential from Molecular Dynamics Simulations in the Presence of Exogenous Electric Fields: The Case Study of Myoglobin

Unfolding Simulations of Holomyoglobin from Four Mammals: Identification of Intermediates and β-Sheet Formation from Partially Unfolded States

Protein Folding and Misfolding: A Perspective from Theory

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