Using collective variables to drive molecular dynamics simulations

Fiorin, Giacomo; Klein, Michael L.; Hénin, Jérôme

doi:10.1080/00268976.2013.813594

Cited by 860 publications

(982 citation statements)

References 74 publications

(121 reference statements)

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“…Within several nanoseconds, the potassium ion bound in site III migrated towards sites I and II. We furthermore used metadynamics simulations (see Experimental procedures) to calculate potential of mean force (PMF) along two collective variables (23) characterizing the bound ion density; the results revealed that protonation of D926 leads to a more favorable binding of K + to binding sites I and II and not to site III ( Figure 1E). Occupation of site III by Na + ions, on the other hand, is consistent with the presence of such a cation in the crystal structure, thus leading us to conclude that D926 should be deprotonated in the Na + -bound E1P state, but not in the K + -bound E2P state.…”

Section: Resultsmentioning

confidence: 99%

Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity

Razavi

Delemotte

Berlin

et al. 2017

Journal of Biological Chemistry

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Na+ /K + -ATPase transports Na + and K + ions across the cell membrane via an ion-binding site becoming alternatively accessible to the intra-and extracellular milieu by conformational transitions that confer marked changes in ion-binding stoichiometry and selectivity. To probe the mechanism of these changes, we used molecular simulation and free energy perturbation approaches to identify probable protonation states of Na + and K + coordinating residues in E1P and E2P conformations of Na + /K + -ATPase. Analysis of these simulations revealed a molecular mechanism responsible for the change in protonation state: the conformation-dependent binding of an anion (a chloride ion in our simulations) to a previously unrecognized cytoplasmic site in the loop between transmembrane helices 8 and 9, which influences the electrostatic potential of the crucial Na + -coordinating residue D926. This mechanistic model is consistent with experimental observations and provides a molecular-level picture of how E1P to E2P enzyme conformational transitions are coupled to changes in ion binding stoichiometry and selectivity. Na + /K + -ATPase is a membrane protein that actively transports sodium ions out of the cell while importing potassium ions, both against their electrochemical gradients, thus providing potential energy necessary for many essential cellular functions (1-3). Malfunction of Na + /K + -ATPase has been linked to numerous diseases including impaired memory and learning, familial hemiplegic migraine 2, rapid-onset dystonia Parkinsonism, and heart failure (4-6), thus, Na + /K + -ATPase is an important target for treatment of brain and heart conditions (7,8).By harnessing chemical energy stored in ATP, the Na + /K + -ATPase cycles between two major conformational states during active ion pumping: one state with high affinity for sodium ions (E1), and a second with high affinity for potassium ion (E2).While the complete mechanism of function of the Na Na+ /K + -ATPase and ion selectivity 2 more complicated, involving several conformational transitions described more fully in the Post-Albers scheme (9-11), here we focus on the sodium-bond E1P and potassium-bound E2P states (i.e. phosphorylated E1 and E2), for which crystal structures are available (12)(13)(14)(15)(16)(17). One of the central features of ion transport by the Na + /K + -ATPase is a change in ion selectivity between E1 and E2 conformations (3). The origin of this selectivity change has been a focus of Na + /K + -ATPase research since its discovery by Jens Christian Skou in 1957 (1). Extensive mutational studies have identified key residues involved in ion binding, which include five acidic residues: Asp804, Asp808, and Asp926, Glu327 and Glu779 (13) whose orientation, distance, and ion coordination have been proposed to be involved in determining selectivity (3). The first crystal structure of the Na + /K + -ATPase, solved for the potassium-bound E2P state in 2007 (15) and later followed by several higher resolution structures (14,16,17), revealed a ...

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Section: Resultsmentioning

confidence: 99%

Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity

Razavi

Delemotte

Berlin

et al. 2017

Journal of Biological Chemistry

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“…This can be done during post processing on the trajectory file, much like a conventional analysis tool, or on-the-fly during the simulation. Other software is available for analyzing existing trajectories [7,20,21,22,23,24] or for biasing MD simulations [15,9,25,26,27,7,6]. PLUMED 2, however, is the only code we know of that allows users to do both sets of tasks with a single syntax.…”

Section: Plumed 2 Overviewmentioning

confidence: 99%

“…Furthermore, given that the interface with the complex MD code was looked after deep within PLUMED and that the coding style of PLUMED was both simple and flexible, it was hoped that developers would use the code to share their methods with the widest possible community. PLUMED has been rather successful in both respects and the plug-in model has been adopted by other researchers [15]. To date there have been approximately 3200 downloads of PLUMED from our website, more than 150 articles in which the original PLUMED article has been cited, more than 200 users who have subscribed to our mailing list, and 20 different super users who have contributed code fragments to our repository.…”

Section: Introductionmentioning

confidence: 99%

PLUMED 2: New feathers for an old bird

Tribello

Bonomi

Branduardi

et al. 2014

Computer Physics Communications

2,901

2,841

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Enhancing sampling and analyzing simulations are central issues in molecular simulation. Recently, we introduced PLUMED, an open-source plug-in that provides some of the most popular molecular dynamics (MD) codes with implementations of a variety of different enhanced sampling algorithms and collective variables (CVs). The rapid changes in this field, in particular new directions in enhanced sampling and dimensionality reduction together with new hardwares, require a code that is more flexible and more efficient. We therefore present PLUMED 2 here -a complete rewrite of the code in an object-oriented programming language (C++). This new version introduces greater flexibility and greater modularity, which both extends its core capabilities and makes it far easier to add new methods and CVs. It also has a simpler interface with the MD engines and provides a single software library containing both tools and core facilities. Ultimately, the new code better serves the ever-growing community of users and contributors in coping with the new challenges arising in the field.

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“…We verified that without this repulsive wall the overlaps occur rarely and only in the last windows of the FEP decoupling procedure; the effect on the estimated free energy is generally comparable to the statistical error. The harmonic restraint as well as the repulsive wall were implemented using the Collective Variables Module available in NAMD 73 .…”

Section: Free Energy Calculationsmentioning

confidence: 99%

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

et al. 2014

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In this work we address the question whether the enhanced stability of thermophilic proteins has a direct connection with internal hydration. Our model systems are two homologues G-domains of different stability: the mesophilic G domain of the Elongation-Factor thermal unstable protein from E. coli and the hyperthermophilic G domain of the EF-α protein from S. solfataricus. Using molecular dynamics simulation at the microsecond time-scale we show that both proteins host water molecules in internal cavities and that these molecules exchange with the external solution in the nanosecond time scale. The hydration free energy of these sites evaluated via extensive calculations is found to be favourable for both systems, with the hyperthermophilic protein offering a slightly more favourable environment to host water molecules. We estimate that under ambient conditions, the free energy gain due to internal hydration is about 1.3 kcal/mol in favor of the hyperthermophilic variant. However, we also find that at the high working temperature of the hyperthermophile, the cavities are rather dehydrated, meaning that at extreme conditions other molecular factors secure the stability of the protein. Interestingly, we detect a clear correlation between the hydration of internal cavities and the protein conformational landscape. The emerging picture is that internal hydration is an effective observable to probe the conformational landscape of proteins. In the specific context of our investigation, the analysis confirms that the hyperthermophilic G-domain is characterized by multiple states and it has a more flexible structure than its mesophilic homologue.

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Using collective variables to drive molecular dynamics simulations

Cited by 860 publications

References 74 publications

Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity

Molecular simulations and free-energy calculations suggest conformation-dependent anion binding to a cytoplasmic site as a mechanism for Na+/K+-ATPase ion selectivity

PLUMED 2: New feathers for an old bird

Role of Internal Water on Protein Thermal Stability: The Case of Homologous G Domains

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