Uncovering Specific Electrostatic Interactions in the Denatured States of Proteins

Shen, Jana

doi:10.1016/j.bpj.2010.05.009

Cited by 29 publications

(65 citation statements)

References 46 publications

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“…It has been discussed previously that small deviations in the Hill coefficient away from 1 have a negligible effect on the free energy 53,54 and, indeed, we find only small differences in n during the curve fitting process. Thus, we have set n ¼ 1 for all our calculations.…”

Section: Constant Ph MD Simulations and Pk A Calculationssupporting

confidence: 73%

“…[47][48][49] Recent studies have shown that CPHMD is a reliable and robust method that is capable of predicting pK a values in a variety of biomolecular systems. [50][51][52][53][54][55][56] Thus, to uncover the pHdependent residues in the CIRV p19 protein involved in siRNA binding stability, we have carried out CPHMD simulations [44][45][46] of the p19 protein dimer in both holo (siRNA-bound) and apo (siRNAfree) forms and determined the pK a values for all titratable residues. These results were then used to calculate the pH-dependent siRNA binding stability profile and corresponding pH-dissociation constant profile.…”

Section: Introductionmentioning

confidence: 99%

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pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

2013

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: Tombusviruses, such as Carnation Italian ringspot virus (CIRV), encode a protein homodimer called p19 that is capable of suppressing RNA silencing in their infected hosts by binding to and sequestering short-interfering RNA (siRNA) away from the RNA silencing pathway. P19 binding stability has been shown to be sensitive to changes in pH but the specific amino acid residues involved have remained unclear. Using constant pH molecular dynamics simulations, we have identified key pH-dependent residues that affect CIRV p19-siRNA binding stability at various pH ranges based on calculated changes in the free energy contribution from each titratable residue. At high pH, the deprotonation of Lys60, Lys67, Lys71, and Cys134 has the largest effect on the binding stability. Similarly, deprotonation of several acidic residues (Asp9, Glu12, Asp20, Glu35, and/or Glu41) at low pH results in a decrease in binding stability. At neutral pH, residues Glu17 and His132 provide a small increase in the binding stability and we find that the optimal pH range for siRNA binding is between 7.0 and 10.0. Overall, our findings further inform recent experiments and are in excellent agreement with data on the pH-dependent binding profile.

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Section: Constant Ph MD Simulations and Pk A Calculationssupporting

confidence: 73%

Section: Introductionmentioning

confidence: 99%

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

2013

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“…58 Clearly, more sophisticated models are needed to capture the entropic and energetic contributions to the nonpolar solvation free energy. Based on the GB simulations of the micelles presented here and simulations of the protein unfolded states, 56 we further suggest that a significant improvement in modeling the conformational states and dynamics of proteins and micelles can be achieved by accounting for the stabilization of solvent-separated conformations. Recent work by Levy and coworkers 59 to include a correction for short-range hydrogen bonding represents an important step toward accurate modeling of the first solvent-shell effects.…”

Section: Discussionmentioning

confidence: 95%

“…For example, recent work has revealed that protein unfolded states are too compact, 56 and the intra-molecular diffusion rate is too low 57 in GB simulations relative to experimental evidence. The parallel between simulations of micelles and protein folding stems from the fact that hydrophobic interactions are the major driving force in both micelle formation and protein folding.…”

Section: Discussionmentioning

confidence: 97%

Molecular dynamics simulations of ionic and nonionic surfactant micelles with a generalized born implicit‐solvent model

et al. 2011

Self Cite

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In recent years, all-atom and coarse-grained models have been developed and applied to simulations of micelles and biological membranes. Here, we explore the question of whether a combined all-atom representation of surfactant molecules and continuum description of solvent based on the generalized Born model can be used to study surfactant micelles. Specifically, we report the parameterization of the GBSW model with a surface-area dependent nonpolar solvation energy term for dodecyl sulfate, dodecyl tetramethylammonium, and dodecyl triethyleneglycol ether molecules. In the parameterization procedure,the atomic Born radii were derived from the radial distribution functions of solvent charge and refined targeting the potential of mean force of dimer interactions from explicit-solvent simulations. The optimized radii were then applied in molecular dynamics simulations of the ionic and nonionic micelles.We found that the micelles are stable but more compact and rigid than in explicit solvent as a consequence of the drastic reduction in solvation and mobility of surfactant monomers within the micelle. Based on these data and our previous work, we suggest that in addition to a more accurate description of the nonpolar solvation energy, the ruggedness in the short-range interactions due to solvent granularity is a critical feature that needs to be taken into account to accurately model processes such as micelle formation and protein folding in implicit solvent. Finally, the explicit-solvent data presented here offers new insights into different conformational behavior of ionic and nonionic micelles which is valuable for understanding hydrophobic assemblies and of interest to the detergent industry.

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“…49 In the native structure of Bax, there is an electrostatic interaction between R134 (aH6) and E41 (Lp1-2). After 5 ns at 300 K [ Fig.…”

Section: Electrostatic Interactions Keep Lp1-2 Close To Lp5-6mentioning

confidence: 99%

Insights into the structural stability of Bax from molecular dynamics simulations at high temperatures

Rosas-Trigueros¹,

Correa‐Basurto²,

Benítez‐Cardoza³

et al. 2011

Protein Science

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Bax is a member of the Bcl-2 protein family that participates in mitochondrion-mediated apoptosis. In the early stages of the apoptotic pathway, this protein migrates from the cytosol to the outer mitochondrial membrane, where it is inserted and usually oligomerizes, making cytochrome c-compatible pores. Although several cellular and structural studies have been reported, a description of the stability of Bax at the molecular level remains elusive. This article reports molecular dynamics simulations of monomeric Bax at 300, 400, and 500 K, focusing on the most relevant structural changes and relating them to biological experimental results. Bax gradually loses its a-helices when it is submitted to high temperatures, yet it maintains its globular conformation. The resistance of Bax to adopt an extended conformation could be due to several interactions that were found to be responsible for maintaining the structural stability of this protein. Among these interactions, we found salt bridges, hydrophobic interactions, and hydrogen bonds. Remarkably, salt bridges were the most relevant to prevent the elongation of the structure. In addition, the analysis of our results suggests which conformational movements are implicated in the activation/oligomerization of Bax. This atomistic description might have important implications for understanding the functionality and stability of Bax in vitro as well as within the cellular environment.

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Uncovering Specific Electrostatic Interactions in the Denatured States of Proteins

Cited by 29 publications

References 46 publications

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

pH‐sensitive residues in the p19 RNA silencing suppressor protein from carnation Italian ringspot virus affect siRNA binding stability

Molecular dynamics simulations of ionic and nonionic surfactant micelles with a generalized born implicit‐solvent model

Insights into the structural stability of Bax from molecular dynamics simulations at high temperatures

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