Limits...
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 (a) ligated and (b) apo LAOBP structures. Note that the color-coding is the same as in Fig. 9, and that panel (a) is exactly the same as Fig. 9a.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2533333&req=5

Figure 11: Cooperativity correlation plots of the (a) ligated and (b) apo LAOBP structures. Note that the color-coding is the same as in Fig. 9, and that panel (a) is exactly the same as Fig. 9a.

Mentions: Differences between the apo/ligated pairs are inline with expectations. In the case of LAOBP, each domain appears as rigidly correlated with itself, whereas the couplings between the two domains are a mix of both weak flexible and rigid correlations (Fig. 11). This result is exactly consistent with the inferred hinge motion from the structural analyses discussed above and demonstrated in Fig. 3. In the case of GBP, the apo structure is significantly destabilized (Δ Tm= 39 K). This fact, coupled with the continuous transition observed within apo GBP, results in a cooperativity correlation plot that, as might be expected, is primarily flexibly correlated.


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 (a) ligated and (b) apo LAOBP structures. Note that the color-coding is the same as in Fig. 9, and that panel (a) is exactly the same as Fig. 9a.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 11: Cooperativity correlation plots of the (a) ligated and (b) apo LAOBP structures. Note that the color-coding is the same as in Fig. 9, and that panel (a) is exactly the same as Fig. 9a.
Mentions: Differences between the apo/ligated pairs are inline with expectations. In the case of LAOBP, each domain appears as rigidly correlated with itself, whereas the couplings between the two domains are a mix of both weak flexible and rigid correlations (Fig. 11). This result is exactly consistent with the inferred hinge motion from the structural analyses discussed above and demonstrated in Fig. 3. In the case of GBP, the apo structure is significantly destabilized (Δ Tm= 39 K). This fact, coupled with the continuous transition observed within apo GBP, results in a cooperativity correlation plot that, as might be expected, is primarily flexibly correlated.

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