Free Energies of Hydration from a Generalized Born Model and an All-Atom Force Field

Jorgensen, William L.; Ulmschneider, and Jakob P.; Tirado‐Rives, Julian

doi:10.1021/jp0484579

Cited by 196 publications

(281 citation statements)

References 44 publications

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“…All simulations used the simple point charge (SPC) model for water (47), the standard OPLS-AA parameters for ions (48,49), and the OPLS-AA/L force field for proteins (28,29) as provided by the program IMPACT (50) (note that the relevant force-field option, referred to as OPLS 2003 in the IMPACT paper, has subsequently been renamed as OPLS 2005 in the actual program). All molecular dynamics simulations were performed by using the parallel MD program Desmond (19) on 64 or 128 dual-processor Opteron nodes connected by a high-speed Infiniband network (Topspin, San Jose, CA).…”

Section: Methodsmentioning

confidence: 99%

A conserved protonation-dependent switch controls drug binding in the Abl kinase

Shan

Seeliger

Eastwood

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

239

314

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In many protein kinases, a characteristic conformational change (the ''DFG flip'') connects catalytically active and inactive conformations. Many kinase inhibitors-including the cancer drug imatinib-selectively target a specific DFG conformation, but the function and mechanism of the flip remain unclear. Using long molecular dynamics simulations of the Abl kinase, we visualized the DFG flip in atomiclevel detail and formulated an energetic model predicting that protonation of the DFG aspartate controls the flip. Consistent with our model's predictions, we demonstrated experimentally that the kinetics of imatinib binding to Abl kinase have a pH dependence that disappears when the DFG aspartate is mutated. Our model suggests a possible explanation for the high degree of conservation of the DFG motif: that the flip, modulated by electrostatic changes inherent to the catalytic cycle, allows the kinase to access flexible conformations facilitating nucleotide binding and release.conformational change ͉ DFG motif ͉ imatinib ͉ molecular dynamics simulation ͉ pH dependence

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Section: Methodsmentioning

confidence: 99%

A conserved protonation-dependent switch controls drug binding in the Abl kinase

Shan

Seeliger

Eastwood

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

239

314

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show abstract

“…All simulations used the OPLS-AA/L force field for protein (53,54) and ions (55) and the simple point charge model for water (56). Lipid parameters were generated as described in ref.…”

Section: Methodsmentioning

confidence: 99%

Dynamic control of slow water transport by aquaporin 0: Implications for hydration and junction stability in the eye lens

Jensen

Dror

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Aquaporin 0 (AQP0), the most abundant membrane protein in mammalian lens fiber cells, not only serves as the primary water channel in this tissue but also appears to mediate the formation of thin junctions between fiber cells. AQP0 is remarkably less water permeable than other aquaporins, but the structural basis and biological significance of this low permeability remain uncertain, as does the permeability of the protein in a reported junctional form. To address these issues, we performed molecular dynamics (MD) simulations of water transport through membrane-embedded AQP0 in both its (octameric) junctional and (tetrameric) nonjunctional forms. From our simulations, we measured an osmotic permeability for the nonjunctional form that agrees with experiment and found that the distinct dynamics of the conserved, lumen-protruding side chains of Tyr-23 and Tyr-149 modulate water passage, accounting for the slow permeation. The junctional and nonjunctional forms conducted water equivalently, in contrast to a previous suggestion based on static crystal structures that water conduction is lost on junction formation. Our analysis suggests that the low water permeability of AQP0 may help maintain the mechanical stability of the junction. We hypothesize that the structural features leading to low permeability may have evolved in part to allow AQP0 to form junctions that both conduct water and contribute to the organizational structure of the fiber cell tissue and microcirculation within it, as required to maintain transparency of the lens.membrane ͉ MD simulation ͉ water channel ͉ permeability ͉ cell adhesion

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“…All MD simulations and analyses were carried out with the Gromacs suite (version 3.3.3) 29 and the OPLS all-atom force field. 30 For the equilibrium MD simulations, the protein was solvated in dodecahedral boxes with at least 5500 TIP4p water molecules 31 under periodic boundary conditions. The typical protonation states at pH 7 were chosen for ionizable groups of the protein and the necessary amount of counter-ions (Cl Ϫ and Na ϩ ) were added to ensure a neutral system of physiologic ion strength.…”

Section: Force-probe MD Simulationsmentioning

confidence: 99%

A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13

Zhou

Dong

Baldauf

et al. 2011

Blood

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The proteolysis of VWF by ADAMTS13 is an essential step in the regulation of its hemostatic and thrombogenic potential. The cleavage occurs at strand ␤4 in the structural core of the A2 domain of VWF, so unfolding of the A2 domain is a prerequisite for cleavage. In the present study, we present the crystal structure of an engineered A2 domain that exhibits a significant difference in the ␣3-␤4 loop compared with the previously reported structure of wild-type A2. Intriguingly, a metal ion was detected at a site formed mainly by the C-terminal region of the ␣3-␤4 loop that was later identified as Ca 2؉ after various biophysical and biochemical studies. Force-probe molecular dynamic simulations of a modeled structure of the wild-type A2 featuring the discovered Ca 2؉ -binding site revealed that an increase in force was needed to unfold strand ␤4 when

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Free Energies of Hydration from a Generalized Born Model and an All-Atom Force Field

Cited by 196 publications

References 44 publications

A conserved protonation-dependent switch controls drug binding in the Abl kinase

A conserved protonation-dependent switch controls drug binding in the Abl kinase

Dynamic control of slow water transport by aquaporin 0: Implications for hydration and junction stability in the eye lens

A novel calcium-binding site of von Willebrand factor A2 domain regulates its cleavage by ADAMTS13

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