A consensus view of protein dynamics

Rueda, Manuel; Ferrer-Costa, Carles; Meyer, Tim; Pérez, Alberto; Camps, Jordi; Hospital, Adam; Gelpí, Josep Lluís; Orozco, Modesto

doi:10.1073/pnas.0605534104

Cited by 218 publications

(275 citation statements)

References 57 publications

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“…Membrane simulations were run for 50 ns after a similar minimization and constrained dynamics scheme as employed for the micelle. Although comparison between different force fields can be complicated, a recent exhaustive simulation study suggests that both force fields are reasonably similar in modeling protein behavior (42). In order to confirm that our comparison of micelle and bilayer results was not overly dependent upon our force field choice, we simulated WT ␣S bound to DOPS using CHARMM (using parameters from Ref.…”

Section: Methodsmentioning

confidence: 99%

Curvature Dynamics of α-Synuclein Familial Parkinson Disease Mutants

Perlmutter

Braun

Sachs

2009

Journal of Biological Chemistry

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␣-Synuclein remains a protein of interest due to its propensity to form fibrillar aggregates in neurodegenerative disease and its putative function in synaptic vesicle regulation. Herein, we present a series of atomistic molecular dynamics simulations of wild-type ␣-synuclein and three Parkinson disease familial mutants (A30P, A53T, and E46K) in two distinct environments. First, in order to match recent NMR experiments, we have simulated each protein bound to an SDS detergent micelle. Second, in order to connect more closely to the true biological environment, we have simulated the proteins bound to a 1,2-dioleoylsn-glycero-3-phosphoserine lipid bilayer. In the micelle-bound case, we find that the wild type and all of the variants of ␣-synuclein flatten the underlying micelle, decreasing its surface area. A30P is known to lessen ␣-synuclein/membrane affinity and, consistent with experiment, destabilizes the simulated secondary structure. In the case of A53T, our simulations reveal a range of stabilizing hydrogen bonds that form with the threonine. In both environments, the E46K mutation, which is known to increase bilayer affinity, leads to an additional hydrogen bond between the protein and either the detergent or lipid. Simulations indicate that ␣S and its variants are less dynamic in the bilayer than in the micelle. Furthermore, the simulations of the mutants suggest how changes in the structure and dynamics of ␣-synuclein may affect its biological role. The main component of fibrous inclusions known as Lewy bodies and Lewy neurites, ␣-synuclein (␣S)2 plays a critical, although as yet not fully understood, role in the onset of Parkinson disease (PD) (1). Three point mutations of ␣S, namely A53T, A30P, and E46K, have been correlated with familial PD (2-4), although it is still unclear exactly how these mutations trigger the disease (5-8). In the case of A30P, a set of recent NMR studies suggest that the proline substitution significantly increases the structural dynamics of the protein when bound to an SDS detergent micelle (9, 10). It is widely accepted that this mutant has reduced binding affinity for membranes, although the extent is somewhat controversial (9,(11)(12)(13)(14)(15)(16)(17). The change in membrane affinity is correlated with a decrease in the helical content of the protein, although again there is considerable debate as to the extent of this effect (9,10,13,16,18). This result is not altogether unexpected; proline disrupts helices due to the loss of a backbone hydrogen bond and steric hindrance between it and neighboring residues (19). The exact effects of proline on a helix, however, can be 2-fold: substitution can cause local unfolding (i.e. total loss of secondary structure) or kinking without loss of helicity. In the case of A30P, current experimental techniques have suggested a loss of helicity upand downstream of the substitution. However, it is still unclear to what extent and where the proline substitution forces unfolding, kinking, or both (9, 10).The other PD familial mutants behave ...

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Section: Methodsmentioning

confidence: 99%

Curvature Dynamics of α-Synuclein Familial Parkinson Disease Mutants

Perlmutter

Braun

Sachs

2009

Journal of Biological Chemistry

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“…The interaction between molecules may be viewed as a motion of a point defining the complex on this hypersurface. Since proteins are quite flexible (Rueda et al, 2007), the number of dimensions of the relevant space may be strongly increased.…”

Section: Theoretical Approach a Theoretical Basis For Bell's Lawmentioning

confidence: 99%

“…v) Simultaneously, computer simulation evolved as a new approach for understanding as well as predicting the behaviour of biomolecules. While thirty years ago, it appeared as a remarkable feat to simulate the behaviour of a few tens of water molecules in a box (Dashevsky and Sarkisov, 1974), it becomes feasible to simulate interactions between proteins comprising thousands of atoms (Schueler-Furman et al, 2005 ;Gray, 2006 ;Rueda et al, 2007) and mimic force-induced bond rupture as studied experimentally on models such as streptavidinbiotin interaction (Zhou et al, 2006).…”

Section: Recent Progress In Studying Molecular Interactionsmentioning

confidence: 99%

What is the biological relevance of the specific bond properties revealed by single‐molecule studies?

Robert

Benoliel

Pierrès

et al. 2007

J of Molecular Recognition

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During the last decade, many authors took advantage of new methodologies based on atomic force microscopy (AFM), biomembrane force probes (BFPs), laminar flow chambers or optical traps to study at the single‐molecule level the formation and dissociation of bonds between receptors and ligands attached to surfaces. Experiments provided a wealth of data revealing the complexity of bond response to mechanical forces and the dependence of bond rupture on bond history. These results supported the existence of multiple binding states and/or reaction pathways. Also, single bond studies allowed us to monitor attachments mediated by a few bonds. The aim of this review is to discuss the impact of this new information on our understanding of biological molecules and phenomena. The following points are discussed: (i) which parameters do we need to know in order to predict the behaviour of an encounter between receptors and ligands, (ii) which information is actually yielded by single‐molecule studies and (iii) is it possible to relate this information to molecular structure? Copyright © 2007 John Wiley & Sons, Ltd.

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“…More than 40 years 1 of intense experimental research have outlined key characteristics of strongly bound water molecules [2][3][4][5] , but the description of the hydration atmosphere generated by mobile and fluctuating water molecules remained more challenging for experimental techniques 1,[6][7][8][9] , fueling the use of theoretical approaches, particularly molecular dynamics (MD) 10,11 as an alternative and often complementary source of information on the average characteristics of protein hydration (as examples see [12][13][14][15][16] ). Thanks to the combination of spectroscopic and MD techniques some aspects of protein hydration have been described, such as the lack of correlation between strong-interacting sites and water residence times 17 , the dynamics of ultra-slow water molecules trapped in protein cavities or channels [17][18][19][20] , or the robustness of the protein hydration to changes in the aminoacidic composition of the proteins 21,22 .…”

Section: Introductionmentioning

confidence: 99%

The Multiple Roles of Waters in Protein Solvation

2017

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Extensive molecular dynamics (MD) simulations have been used to characterize the multiple roles of water in solvating different types of proteins under different environmental conditions. We analyzed a small set of proteins, representative of the most prevalent meta-folds under native conditions, in the presence of crowding agents, and at high temperature with or without high concentration of urea. We considered also a protein in the unfolded state as characterized by NMR and atomistic MD simulations. Our results outline the main characteristics of the hydration environment of proteins and illustrate the dramatic plasticity of water, and its chameleonic ability to stabilize proteins under a variety of conditions.

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A consensus view of protein dynamics

Cited by 218 publications

References 57 publications

Curvature Dynamics of α-Synuclein Familial Parkinson Disease Mutants

Curvature Dynamics of α-Synuclein Familial Parkinson Disease Mutants

What is the biological relevance of the specific bond properties revealed by single‐molecule studies?

The Multiple Roles of Waters in Protein Solvation

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