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

(a) Heat capacity curves and (b) free energy landscapes of the four ligated bPBP homologs. In (c) and (d) the heat capacity curves and free energy landscapes, respectively, of the apo structures (dashed lines) are compared to the ligated counterparts. Color coding is conserved throughout.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: (a) Heat capacity curves and (b) free energy landscapes of the four ligated bPBP homologs. In (c) and (d) the heat capacity curves and free energy landscapes, respectively, of the apo structures (dashed lines) are compared to the ligated counterparts. Color coding is conserved throughout.

Mentions: Employing the HBP best-fit parameters (Table 1) for each of the four ligated structures, their predicted Cp curves as a function of temperature, relative to their predicted melting temperature (i.e. T – Tm), (see Fig. 5a) shows a high degree of diversity. For example, the maximal Cp ranges from 26.4 kcal/(mol·K) for GBP to 174.1 kcal/(mol·K) for PhBP. These differences are not particularly surprising, and, moreover, the underlying H-bond networks explain the variation within the heat capacities. For example, greater H-bond numbers is strongly correlated with Cpmax (R = 0.90). Similarly, Cpmax is also strongly correlated to the number of residues within the protein (R = 0.87), which occurs because the number of H-bonds and the number of residues are almost perfectly correlated (R = 0.99). Across the four structures, the average number of H-bonds per residue is 1.47 (standard deviation = 0.08). Based on Eq. (4), the effect of H-bond numbers and total H-bond energy on Cp can be conceptualized. Greater H-bond numbers provide more opportunities for enthalpic fluctuations to occur, thus increasing the Cp. In the same manner, the total H-bond energies, Uhbmax, are even more strongly correlated to Cpmax (R = -0.97). A large part of this relationship is explained by the fact the number of H-bonds is, of course, strongly related to the total H-bond energy (R = -0.97). However, the increased correlation to Cpmax is due to the greater effect upon the total enthalpy when a stronger H-bond is removed.


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)

(a) Heat capacity curves and (b) free energy landscapes of the four ligated bPBP homologs. In (c) and (d) the heat capacity curves and free energy landscapes, respectively, of the apo structures (dashed lines) are compared to the ligated counterparts. Color coding is conserved throughout.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: (a) Heat capacity curves and (b) free energy landscapes of the four ligated bPBP homologs. In (c) and (d) the heat capacity curves and free energy landscapes, respectively, of the apo structures (dashed lines) are compared to the ligated counterparts. Color coding is conserved throughout.
Mentions: Employing the HBP best-fit parameters (Table 1) for each of the four ligated structures, their predicted Cp curves as a function of temperature, relative to their predicted melting temperature (i.e. T – Tm), (see Fig. 5a) shows a high degree of diversity. For example, the maximal Cp ranges from 26.4 kcal/(mol·K) for GBP to 174.1 kcal/(mol·K) for PhBP. These differences are not particularly surprising, and, moreover, the underlying H-bond networks explain the variation within the heat capacities. For example, greater H-bond numbers is strongly correlated with Cpmax (R = 0.90). Similarly, Cpmax is also strongly correlated to the number of residues within the protein (R = 0.87), which occurs because the number of H-bonds and the number of residues are almost perfectly correlated (R = 0.99). Across the four structures, the average number of H-bonds per residue is 1.47 (standard deviation = 0.08). Based on Eq. (4), the effect of H-bond numbers and total H-bond energy on Cp can be conceptualized. Greater H-bond numbers provide more opportunities for enthalpic fluctuations to occur, thus increasing the Cp. In the same manner, the total H-bond energies, Uhbmax, are even more strongly correlated to Cpmax (R = -0.97). A large part of this relationship is explained by the fact the number of H-bonds is, of course, strongly related to the total H-bond energy (R = -0.97). However, the increased correlation to Cpmax is due to the greater effect upon the total enthalpy when a stronger H-bond is removed.

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