Do salt bridges stabilize proteins? A continuum electrostatic analysis

Hendsch, Zachary S.; Tidor, Bruce

doi:10.1002/pro.5560030206

Cited by 643 publications

(723 citation statements)

References 68 publications

Supporting

Mentioning

682

Contrasting

Unclassified

Order By: Relevance

“…The fact that the salt bridge is not stable (no more stable than the Thr-Glu contact) suggests that it does not contribute significantly to the stability of the molecule. This is in accord with the general analysis of salt bridges by Hendsch and Tidor (1994). Contact #25, an LI-L2 hydrophobic contact, flickers more in RdPf than in RdDv.…”

Section: Structural Aspectssupporting

confidence: 88%

“…In other cases, this correlation should not be expected. For example, the introduction of a salt bridge in the protein interior tends to make the protein more rigid, but at the same time can destabilize it thermodynamically (Hendsch & Tidor, 1994;Waldburger et al, 1995). A thermostable disulfide-bridged mutant of T4 lysozyme exhibited similar temperature factors in the crystal as the wild type (Pjura et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Dynamics and unfolding pathways of a hyperthermophilic and a mesophilic rubredoxin

1997

View full text Add to dashboard Cite

Molecular dynamics simulations in solution are performed for a rubredoxin from the hyperthermophilic archaeon Pymcoccus furiosus (RdPf) and one from the mesophilic organism Desulfovibrio vulgaris (RdDv). The two proteins are simulated at four temperatures: 300 K, 373 K, 473 K (two sets), and 500 K; the various simulations extended from 200 ps to 1,020 ps. At room temperature, the two proteins are stable, remain close to the crystal structure, and exhibit similar dynamic behavior; the RMS residue fluctuations are slightly smaller in the hyperthermophilic protein. An analysis of the average energy contributions in the two proteins is made; the results suggest that the intraprotein energy stabilizes RdPf relative to RdDv. At 373 K, the mesophilic protein unfolds rapidly (it begins to unfold at 300 ps), whereas the hyperthermophilic does not unfold over the simulation of 600 ps. This is in accord with the expected stability of the two proteins. At 473 K, where both proteins are expected to be unstable, unfolding behavior is observed within 200 ps and the mesophilic protein unfolds faster than the hyperthermophilic one. At 500 K, both proteins unfold; the hyperthermophilic protein does so faster than the mesophilic protein. The unfolding behavior for the two proteins is found to be very similar. Although the exact order of events differs from one trajectory to another, both proteins unfold first by opening of the loop region to expose the hydrophobic core. This is followed by unzipping of the @-sheet. The results obtained in the simulation are discussed in terms of the factors involved in flexibility and thermostability.

show abstract

Section: Structural Aspectssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Dynamics and unfolding pathways of a hyperthermophilic and a mesophilic rubredoxin

1997

View full text Add to dashboard Cite

show abstract

“…However, the current results suggest that this is not the case. Both the experimental and computational results suggest Glu-Lys pairs in a β-sheet are generally unfavorable compared with hydrophobic interactions burying a similar amount of total surface 26,27 . Then, what is the role of the abundant Glu and Lys residues in the single-layer β-sheet?…”

Section: Design Features Of the Ospa Single-layer β-Sheetmentioning

confidence: 97%

Hydrophobic Surface Burial Is the Major Stability Determinant of a Flat, Single-layer β-Sheet

Yan¹,

Gawlak²,

Makabe³

et al. 2007

Journal of Molecular Biology

View full text Add to dashboard Cite

Formation of a flat β-sheet is a fundamental event in β-sheet-mediated protein self-assembly. To investigate contributions of various factors to the stability of flat β-sheets, we performed extensive alanine-scanning mutagenesis experiments on the single-layer β-sheet segment of Borrelia outer surface protein A (OspA). This β-sheet segment consists of β-strands with highly regular geometries that can serve as a building block for self-assembly. Our Ala-scanning approach is distinct from the conventional host-guest method in that it introduces only conservative, truncation mutations that should minimize structural perturbation. Our results showed very weak correlation with experimental β-sheet propensity scales, statistical β-sheet propensity scales, or cross-strand pairwise correlations. In contrast, our data showed strong positive correlation with the change in buried nonpolar surface area. Polar interactions including prominent Glu-Lys cross-strand pairs marginally contribute to the β-sheet stability. These results were corroborated by results from additional non-Ala mutations. Taken together, these results demonstrate the dominant contribution of nonpolar surface burial to flat β-sheet stability even at solvent-exposed positions. The OspA single-layer β-sheet achieves efficient hydrophobic surface burial without forming a hydrophobic core by a strategic placement of a variety of side chains. These findings further suggest the importance of hydrophobic interactions within a β-sheet layer in peptide self-assembly.

show abstract

“…A well-understood example in protein chemistry is interactions between opposing charges in protein structures. Formation of such interactions require removal of the charges from bulk water, which comes with a substantial, unfavorable "desolvation" penalty (26,27). The coulombic energy from the interaction between the charges is often insufficient to offset the desolvation penalty (28).…”

mentioning

confidence: 99%

How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

Blevins

Pierce

Singh

et al. 2016

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

View full text Add to dashboard Cite

How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining αβ TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the α1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Vα and Vβ genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.T-cell receptor | peptide/MHC | structure | binding | MHC bias

show abstract

Do salt bridges stabilize proteins? A continuum electrostatic analysis

Cited by 643 publications

References 68 publications

Dynamics and unfolding pathways of a hyperthermophilic and a mesophilic rubredoxin

Dynamics and unfolding pathways of a hyperthermophilic and a mesophilic rubredoxin

Hydrophobic Surface Burial Is the Major Stability Determinant of a Flat, Single-layer β-Sheet

How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

Contact Info

Product

Resources

About