Exploring atomistic details of pH-dependent peptide folding

Khandogin, Jana; Chen, Jianhan; Brooks, Charles L.

doi:10.1073/pnas.0605216103

Cited by 87 publications

(105 citation statements)

References 24 publications

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“…It should be noted that our simulations used a recently improved implicit solvent model, GB with a simple switching (GBSW) (14,15). Its application to protein folding studies has been validated by comparison between simulated and experimental folding behavior for a series of helix-and ␤-sheet-based peptides (15,17).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, this method enables molecular dynamics simulations to be performed simultaneously with the titration of ionizable side chains under an external pH condition in the presence of a generalized Born (GB) implicit solvent model. Combined with a state-of-the-art conformational sampling protocol, the REX algorithm (13), benchmark studies demonstrated that REX-CPHMD simulations can offer accurate and robust first-principles prediction for protein pK a values (16) and atomically detailed molecular mechanisms for pHdependent protein folding (17,18). It should be noted that our simulations used a recently improved implicit solvent model, GB with a simple switching (GBSW) (14,15).…”

Section: Methodsmentioning

confidence: 99%

“…Combined with a state-of-the-art conformational sampling protocol, the replica-exchange (REX) algorithm (13), and an improved continuum solvent model (14, 15), this method has opened a door to first-principles pK a prediction for proteins (16) and theoretical studies of pH-dependent conformational processes in biology (17,18). We now use REX-CPHMD simulations to explore the folding of two model peptides, A␤(1-28) and A␤(10-42).…”

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confidence: 99%

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Linking folding with aggregation in Alzheimer's β-amyloid peptides

Khandogin

Brooks²

2007

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

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148

202

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Growing evidence suggests that the ␤-amyloid (A␤) peptides of Alzheimer's disease are generated in early endosomes and that small oligomers are the principal toxic species. We sought to understand whether and how the solution pH, which is more acidic in endosomes than the extracellular environment, affects the conformational processes of A␤. Using constant pH molecular dynamics simulations of two model peptides, A␤(1-28) and A␤(10 -42), we found that the folding landscape of A␤ is strongly modulated by pH and is most favorable for hydrophobically driven aggregation at pH 6. Thus, our theoretical findings substantiate the possibility that A␤ oligomers develop intracellularly before secretion into the extracellular milieu, where they may disrupt synaptic activity or act as seeds for plaque formation.␤-turn ͉ helix ͉ pH-dependent ͉ molecular dynamics ͉ electrostatics P rotein aggregation and fibril formation have been implicated in a number of human diseases, including amyloidoses and neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) that are most prevalent in aged populations. Although it is now widely known that the initial aggregation step for globular proteins involves the formation of a partially unfolded monomeric intermediate (1), little is understood for natively unfolded proteins such as the ␤-amyloid (A␤) peptides of AD and the ␣-synuclein protein of PD. To elucidate the conformational behavior of A␤, fragments as well as the full-length (40 or 42 residues) monomers have been intensively studied by spectroscopic techniques such as circular dichroism (CD) and solution NMR in both water and aqueous solutions of TFE, a cosolvent known to stabilize local hydrogen bonding in peptides with intrinsic helix propensity (2). In water, A␤ peptides have been characterized as mainly unfolded (3, 4) whereas in TFE solution, they display a pH-dependent helix profile with a minimum helix content centered around pH 5.5 (3). An early study showed that A␤(1-28) forms mature fibrils only in the pH range between 3 and 8 (5). A recent kinetics experiment revealed that the full-length A␤ aggregates most rapidly at pH 4-5.7 (6). However, conformational transitions in the early aggregation step as well as its relationship to pH remain unknown. Understanding the role of environmental conditions such as solution pH in the oligomerization of A␤ is important, because increasing experimental data suggest that A␤ is cleaved from the amyloid precursor protein in early endosomes, which have a pH of Ϸ6 (7,8) and that dimers and trimers are necessary and sufficient to disrupt synaptic activity (9, 10).We have recently developed the continuous constant pH molecular dynamics (CPHMD) method (11, 12), which allows conformational dynamics to be microscopically coupled with protonation equilibria in the atomic-level simulation of biological macromolecules. Combined with a state-of-the-art conformational sampling protocol, the replica-exchange (REX) algorithm (13), and an improved continuum solvent model (1...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Linking folding with aggregation in Alzheimer's β-amyloid peptides

Khandogin

Brooks²

2007

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

Self Cite

148

202

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“…[1][2][3][4][5] In the continuous approach, an additional titration degree of freedom is added for every titratable site and the titration degrees of freedom are propagated alongside conformational dynamics. [6][7][8] Among these methods, the continuous pH molecular dynamics (pHMD) method 7,8 based on λ dynamics, 9 which will be referred to as CpHMD hereafter, has been successfully applied to pK a predictions 10 and pH-dependent protein folding 11 and conformational dynamics. 12,13 The first version of the CpHMD technique makes use of the generalized Born (GB) implicit-solvent model for propagating both conformational and titration coordinates and the temperature-based a) Present address: Department of Pharmaceutical Sciences, University of Maryland, Baltimore, Maryland 21201, USA.…”

Section: Introductionmentioning

confidence: 99%

Charge-leveling and proper treatment of long-range electrostatics in all-atom molecular dynamics at constant pH

Wallace

Shen²

2012

The Journal of Chemical Physics

102

178

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Recent development of constant pH molecular dynamics (CpHMD) methods has offered promise for adding pH-stat in molecular dynamics simulations. However, until now the working pH molecular dynamics (pHMD) implementations are dependent in part or whole on implicit-solvent models. Here we show that proper treatment of long-range electrostatics and maintaining charge neutrality of the system are critical for extending the continuous pHMD framework to the all-atom representation. The former is achieved here by adding forces to titration coordinates due to long-range electrostatics based on the generalized reaction field method, while the latter is made possible by a charge-leveling technique that couples proton titration with simultaneous ionization or neutralization of a co-ion in solution. We test the new method using the pH-replica-exchange CpHMD simulations of a series of aliphatic dicarboxylic acids with varying carbon chain length. The average absolute deviation from the experimental pK a values is merely 0.18 units. The results show that accounting for the forces due to extended electrostatics removes the large random noise in propagating titration coordinates, while maintaining charge neutrality of the system improves the accuracy in the calculated electrostatic interaction between ionizable sites. Thus, we believe that the way is paved for realizing pH-controlled all-atom molecular dynamics in the near future.

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“…The strength of the charge-charge interaction depends on the distance as 1/r, which makes them, at short distances, comparable in strength with Lennard-Jones (LJ) interactions. However, the charge-charge interactions are also long-range and they do not decay as quickly as LJ with the increase in distance [40][41][42][43][44]. All this makes charge-charge interactions an important contributor not only to protein stability, but also to the overall behavior of polypeptide sequences as heteropolymers [45,46].…”

Section: Introductionmentioning

confidence: 99%

Linking computation and experiments to study the role of charge–charge interactions in protein folding and stability

Makhatadze

2017

Phys. Biol.

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Over the past two decades there has been an increase in appreciation for the role of surface chargecharge interactions in protein folding and stability. The perception shifted from the belief that chargecharge interactions are not important for protein folding and stability to the near quantitative understanding of how these interactions shape the folding energy landscape. This led to the ability of computational approaches to rationally redesign surface charge-charge interactions to modulate thermodynamic properties of proteins. Here we summarize our progress in understanding the role of charge-charge interactions for protein stability using examples drawn from my own laboratory and touch upon unanswered questions.

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Exploring atomistic details of pH-dependent peptide folding

Cited by 87 publications

References 24 publications

Linking folding with aggregation in Alzheimer's β-amyloid peptides

Linking folding with aggregation in Alzheimer's β-amyloid peptides

Charge-leveling and proper treatment of long-range electrostatics in all-atom molecular dynamics at constant pH

Linking computation and experiments to study the role of charge–charge interactions in protein folding and stability

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