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Hydrogen bond networks determine emergent mechanical and thermodynamic properties across a protein family.

Livesay DR, Huynh DH, Dallakyan S, Jacobs DJ - Chem Cent J (2008)

Bottom Line: Nevertheless, significant differences are found in molecular cooperativity correlations that can be explained by the detailed nature of the hydrogen bond network.This inference is consistent with well-known results that show allosteric response within a family generally varies significantly.Identifying the hydrogen bond network as a critical determining factor for these large variances may lead to new methods that can predict such effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Computer Science and Bioinformatics Research Center, University of North Carolina at Charlotte, Charlotte, NC, USA. drlivesa@uncc.edu

ABSTRACT

Background: Gram-negative bacteria use periplasmic-binding proteins (bPBP) to transport nutrients through the periplasm. Despite immense diversity within the recognized substrates, all members of the family share a common fold that includes two domains that are separated by a conserved hinge. The hinge allows the protein to cycle between open (apo) and closed (ligated) conformations. Conformational changes within the proteins depend on a complex interplay of mechanical and thermodynamic response, which is manifested as an increase in thermal stability and decrease of flexibility upon ligand binding.

Results: We use a distance constraint model (DCM) to quantify the give and take between thermodynamic stability and mechanical flexibility across the bPBP family. Quantitative stability/flexibility relationships (QSFR) are readily evaluated because the DCM links mechanical and thermodynamic properties. We have previously demonstrated that QSFR is moderately conserved across a mesophilic/thermophilic RNase H pair, whereas the observed variance indicated that different enthalpy-entropy mechanisms allow similar mechanical response at their respective melting temperatures. Our predictions of heat capacity and free energy show marked diversity across the bPBP family. While backbone flexibility metrics are mostly conserved, cooperativity correlation (long-range couplings) also demonstrate considerable amount of variation. Upon ligand removal, heat capacity, melting point, and mechanical rigidity are, as expected, lowered. Nevertheless, significant differences are found in molecular cooperativity correlations that can be explained by the detailed nature of the hydrogen bond network.

Conclusion: Non-trivial mechanical and thermodynamic variation across the family is explained by differences within the underlying H-bond networks. The mechanism is simple; variation within the H-bond networks result in altered mechanical linkage properties that directly affect intrinsic flexibility. Moreover, varying numbers of H-bonds and their strengths control the likelihood for energetic fluctuations as H-bonds break and reform, thus directly affecting thermodynamic properties. Consequently, these results demonstrate how unexpected large differences, especially within cooperativity correlation, emerge from subtle differences within the underlying H-bond network. This inference is consistent with well-known results that show allosteric response within a family generally varies significantly. Identifying the hydrogen bond network as a critical determining factor for these large variances may lead to new methods that can predict such effects.

No MeSH data available.


Related in: MedlinePlus

Cooperativity correlation plots of the ligated (a) LAOBP, (b) HBP, (c) GBP, and (d) PhBP structures. Red indicates flexibly correlated regions, blue indicates rigidly correlated regions, and white indicates regions of no correlation.
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Figure 10: Cooperativity correlation plots of the ligated (a) LAOBP, (b) HBP, (c) GBP, and (d) PhBP structures. Red indicates flexibly correlated regions, blue indicates rigidly correlated regions, and white indicates regions of no correlation.

Mentions: In previous work [22], we demonstrated that cooperativity correlation is moderately conserved across an orthologous RNase H pair. However, this is clearly not the case here; juxtaposed to the flexibility conservation along the backbone, there is immense variation within cooperativity correlation (see Fig. 10). In all cases, the large domain is primarily composed of one large rigid cluster, which results in rigidity correlation in each of the four corners (because the domain is interrupted) of the cooperativity correlation plots. Conversely, the small domain demonstrates much variability within its cooperativity correlation. The small domain generally contains flexibly and rigidly correlated regions within itself and extending into the larger domain. However, the small domain in LAOBP is mostly rigidly correlated with itself and the rest of the protein, indicating that it is primarily composed on one larger rigid cluster. These differences will be discussed again below.


Hydrogen bond networks determine emergent mechanical and thermodynamic properties across a protein family.

Livesay DR, Huynh DH, Dallakyan S, Jacobs DJ - Chem Cent J (2008)

Cooperativity correlation plots of the ligated (a) LAOBP, (b) HBP, (c) GBP, and (d) PhBP structures. Red indicates flexibly correlated regions, blue indicates rigidly correlated regions, and white indicates regions of no correlation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2533333&req=5

Figure 10: Cooperativity correlation plots of the ligated (a) LAOBP, (b) HBP, (c) GBP, and (d) PhBP structures. Red indicates flexibly correlated regions, blue indicates rigidly correlated regions, and white indicates regions of no correlation.
Mentions: In previous work [22], we demonstrated that cooperativity correlation is moderately conserved across an orthologous RNase H pair. However, this is clearly not the case here; juxtaposed to the flexibility conservation along the backbone, there is immense variation within cooperativity correlation (see Fig. 10). In all cases, the large domain is primarily composed of one large rigid cluster, which results in rigidity correlation in each of the four corners (because the domain is interrupted) of the cooperativity correlation plots. Conversely, the small domain demonstrates much variability within its cooperativity correlation. The small domain generally contains flexibly and rigidly correlated regions within itself and extending into the larger domain. However, the small domain in LAOBP is mostly rigidly correlated with itself and the rest of the protein, indicating that it is primarily composed on one larger rigid cluster. These differences will be discussed again below.

Bottom Line: Nevertheless, significant differences are found in molecular cooperativity correlations that can be explained by the detailed nature of the hydrogen bond network.This inference is consistent with well-known results that show allosteric response within a family generally varies significantly.Identifying the hydrogen bond network as a critical determining factor for these large variances may lead to new methods that can predict such effects.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Computer Science and Bioinformatics Research Center, University of North Carolina at Charlotte, Charlotte, NC, USA. drlivesa@uncc.edu

ABSTRACT

Background: Gram-negative bacteria use periplasmic-binding proteins (bPBP) to transport nutrients through the periplasm. Despite immense diversity within the recognized substrates, all members of the family share a common fold that includes two domains that are separated by a conserved hinge. The hinge allows the protein to cycle between open (apo) and closed (ligated) conformations. Conformational changes within the proteins depend on a complex interplay of mechanical and thermodynamic response, which is manifested as an increase in thermal stability and decrease of flexibility upon ligand binding.

Results: We use a distance constraint model (DCM) to quantify the give and take between thermodynamic stability and mechanical flexibility across the bPBP family. Quantitative stability/flexibility relationships (QSFR) are readily evaluated because the DCM links mechanical and thermodynamic properties. We have previously demonstrated that QSFR is moderately conserved across a mesophilic/thermophilic RNase H pair, whereas the observed variance indicated that different enthalpy-entropy mechanisms allow similar mechanical response at their respective melting temperatures. Our predictions of heat capacity and free energy show marked diversity across the bPBP family. While backbone flexibility metrics are mostly conserved, cooperativity correlation (long-range couplings) also demonstrate considerable amount of variation. Upon ligand removal, heat capacity, melting point, and mechanical rigidity are, as expected, lowered. Nevertheless, significant differences are found in molecular cooperativity correlations that can be explained by the detailed nature of the hydrogen bond network.

Conclusion: Non-trivial mechanical and thermodynamic variation across the family is explained by differences within the underlying H-bond networks. The mechanism is simple; variation within the H-bond networks result in altered mechanical linkage properties that directly affect intrinsic flexibility. Moreover, varying numbers of H-bonds and their strengths control the likelihood for energetic fluctuations as H-bonds break and reform, thus directly affecting thermodynamic properties. Consequently, these results demonstrate how unexpected large differences, especially within cooperativity correlation, emerge from subtle differences within the underlying H-bond network. This inference is consistent with well-known results that show allosteric response within a family generally varies significantly. Identifying the hydrogen bond network as a critical determining factor for these large variances may lead to new methods that can predict such effects.

No MeSH data available.


Related in: MedlinePlus