Exploring protein native states and large‐scale conformational changes with a modified generalized born model

Onufriev, Alexey V.; Bashford, Donald; Case, David A.

doi:10.1002/prot.20033

Cited by 2,243 publications

(2,349 citation statements)

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“…3. Normal modes and trajectories of mode displacements were additionally calculated from the same structure used in the elastic normal mode calculations using GROMACS with the CHARMM27 force field combined with the OBC (Onufriev, Bashford, Case) implicit solvent model 51 . The structure was thoroughly minimized to reach a minimum before the normal mode analysis was made in GROMACS 52 .…”

Section: Methodsmentioning

confidence: 99%

Correlated motions are a fundamental property of β-sheets

et al. 2014

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Correlated motions in proteins can mediate fundamental biochemical processes such as signal transduction and allostery. The mechanisms that underlie these processes remain largely unknown due mainly to limitations in their direct detection. Here, based on a detailed analysis of protein structures deposited in the protein data bank, as well as on state-of-the art molecular simulations, we provide general evidence for the transfer of structural information by correlated backbone motions, mediated by hydrogen bonds, across b-sheets. We also show that the observed local and long-range correlated motions are mediated by the collective motions of b-sheets and investigate their role in large-scale conformational changes. Correlated motions represent a fundamental property of b-sheets that contributes to protein function.

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Section: Methodsmentioning

confidence: 99%

Correlated motions are a fundamental property of β-sheets

et al. 2014

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“…The Onufriev− Bashford−Case implicit solvent model was chosen to represent the solution environment around the protein in order to avoid possible confined aqueous volume effects and specific heat errors on the simulated structures. 5,6,41,42 Particle mesh Ewald method was used to treat the long-range interactions using a cutoff value of 25 Å. 46,47 The temperature was maintained by employing Langevin dynamics with a collision frequency of 2 ps −1 .…”

Section: ■ Methodsmentioning

confidence: 99%

“…One approach that has been widely used for the simulations of disordered proteins is the parallel tempering method. 41,42 Such simulations help to increase the conformational sampling in comparison to classical MD simulations without the application of special sampling techniques, which can be trapped in one specific potential minimum. 4−8,12,19,20,22,32−37 Using parallel tempering MD simulations, we studied the structural properties including the secondary and tertiary structures as well as the free energy landscapes of the wild-and R5A mutant-type Aβ42 peptides in an aqueous solution medium and compared these characteristics to one another.…”

Section: Aβ42 Presented In Bold: D a E F R H D S G Y E V H H Q K L Vmentioning

confidence: 99%

Arginine and Disordered Amyloid-β Peptide Structures: Molecular Level Insights into the Toxicity in Alzheimer’s Disease

Coskuner

Wise-Scira

2013

ACS Chem. Neurosci.

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Recent studies present that the single arginine (R) residue in the sequence of Aβ42 adopts abundant β-sheet structure and forms stable salt bridges with various residues. Furthermore, experiments proposed that R stimulates the Aβ assembly and arginine (R) to alanine (A) mutation (R5A) decreases both aggregate formation tendency and the degree of its toxicity. However, the exact roles of R and R5A mutation in the structures of Aβ42 are poorly understood. Extensive molecular dynamics simulations along with thermodynamic calculations present that R5A mutation impacts the structures and free energy landscapes of the aqueous Aβ42 peptide. The β-sheet structure almost disappears in the Ala21−Ala30 region but is more abundant in parts of the central hydrophobic core and C-terminal regions of Aβ42 upon R5A mutation. More abundant α-helix is adopted in parts of the N-terminal and mid-domain regions and less prominent α-helix formation occurs in the central hydrophobic core region of Aβ42 upon R5A mutation. Interestingly, intramolecular interactions between N-and C-terminal or mid-domain regions disappear upon R5A mutation. The structures of Aβ42 are thermodynamically less stable and retain reduced compactness upon R5A mutation. R5A mutant-type structure stability increases with more prominent central hydrophobic core and mid-domain or C-terminal region interactions. Based on our results reported in this work, small organic molecules and antibodies that avoid β-sheet formation in the Ala21−Ala30 region and hinder the intramolecular interactions occurring between the N-terminal and mid-domain or C-terminal regions of Aβ42 may help to reduce Aβ42 toxicity in Alzheimer's disease.

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“…Solvent effects were modelled implicitly with the generalized Born model-II of Onufriev et al 35 , which is implemented in Amber 8. The dielectric constants of 1 and 78.5 were used for the protein interior and solvent regions, respectively.…”

Section: Generalized Born Simulationsmentioning

confidence: 99%

A Fluid Salt-bridging Cluster and the Stabilization of p53

Lwin¹,

Durant²,

Bashford³

2007

Journal of Molecular Biology

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Abstractp53 is a homotetrameric tumor suppressor protein that is found to be mutated in most human cancers. Some of these mutations, particularly mutations to R337 fall in the tetramerization domain and cause defects in tetramer formation leading to loss of function. Mutation to His at this site has been found to destabilize the tetramer in a pH-dependent fashion. In structures of the tet domain determined by crystallography, R337 from one monomer makes a salt bridge with D352 from another monomer, apparently helping to stabilize the tetramer. Here we present molecular dynamics simulations of wildtype p53 and the R337His mutant at several different pH and salt conditions. We find that the 337-352 salt bridge is joined by two other charged sidechains, R333 and E349. These four residues do not settle into a fixed pattern of salt-bridging, but continue to exchange salt-bridging partners on the nanosecond timescale throughout the simulation. This unusual system of fluid salt-bridging may explain the previous finding from alanine scanning experiments that R333 contributes significantly to protein stability even though, in the crystal structure it is extended outward into solvent. This extended conformation of R333 appears to be the result of a specific crystal contact and, this contact being absent in the simulation, R333 turns inward to join its interaction partners. When R337 is mutated to His but remains positively charged, it maintains the original interaction with D352, but the newly observed interaction with E349 is weakened, accounting for the reduced stability of R337H even under mildly acidic conditions. When this His is deprotonated, the interaction with D352 is also lost, accounting for the further destabilization observed under mildly alkaline conditions. Simulations were carried out using both explicit and implicit solvent models, and both displayed similar behavior of the fluid salt-bridging cluster, suggesting that implicit solvent models can capture at least the qualitative features of this phenomenon as well as explicit solvent. Simulations under strongly acidic conditions in implicit solvent displayed the beginnings of the unfolding process, a destabilization of the hydrophobic dimer-dimer interface. Computational alanine scanning using the MM/PBSA method showed significant correlation to experimental unfolding data for charged and polar residues, but much weaker correlation for hydrophobic residues.⋆ We thank Richard Kriwacki and Charles Galea for helpful discussions and advance access to NH-exchange data. Computing resources were provided by the

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Exploring protein native states and large‐scale conformational changes with a modified generalized born model

Cited by 2,243 publications

References 37 publications

Correlated motions are a fundamental property of β-sheets

Correlated motions are a fundamental property of β-sheets

Arginine and Disordered Amyloid-β Peptide Structures: Molecular Level Insights into the Toxicity in Alzheimer’s Disease

A Fluid Salt-bridging Cluster and the Stabilization of p53

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