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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

(a) Structure superposition of the ligated (blue) and apo (red) LAOBP conformations as calculated by the combinatorial extension algorithm. The overall RMSD between the two conformations is 3.5 Å. Structure superposition of the (b) large and (c) small domains is also provided. The domain specific RMSDs are 0.6 Å and 0.4 Å, respectively.
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Figure 3: (a) Structure superposition of the ligated (blue) and apo (red) LAOBP conformations as calculated by the combinatorial extension algorithm. The overall RMSD between the two conformations is 3.5 Å. Structure superposition of the (b) large and (c) small domains is also provided. The domain specific RMSDs are 0.6 Å and 0.4 Å, respectively.

Mentions: From the superposition of the apo and ligated LAOBP conformations (Fig. 3a), it is clear that there is pronounced conformational changes on ligand binding. In fact, the RMSD between the two LAOBP conformations is 3.5 Å. Similarly, the pairwise RMSD between the GBP pair is 4.0 Å. Although the RMSD values reported in Table 3 represent overall dissimilarity between pairs, this does not properly describe local similarities because members of the bPBP family are composed of two domains connected by a flexible linker that allows the protein to transition from apo and ligated conformations. SCOP does not discriminate between the two domains; nevertheless, common domain identification algorithms (i.e., PDP [40] and DomainParser [41,42]) do identify the two domains. In Table 2, the PDP domain boundaries are indicated. Note that the large domain is interrupted by insertion of the small one, resulting in two linkers across the domain boundary. The calculated pairwise RMSD between the large and small LAOBP domains individually is 0.4 Å and 0.6 Å, respectively (see Fig. 3b–c). (The corresponding RMSDs between the GBP domains are 0.6 Å and 0.8 Å.) These strong domain-specific similarities indicate that the large and small domains move more or less intact upon ligand binding, which is indicative of a hinge-like motion at the domain boundaries [43].


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) Structure superposition of the ligated (blue) and apo (red) LAOBP conformations as calculated by the combinatorial extension algorithm. The overall RMSD between the two conformations is 3.5 Å. Structure superposition of the (b) large and (c) small domains is also provided. The domain specific RMSDs are 0.6 Å and 0.4 Å, respectively.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 3: (a) Structure superposition of the ligated (blue) and apo (red) LAOBP conformations as calculated by the combinatorial extension algorithm. The overall RMSD between the two conformations is 3.5 Å. Structure superposition of the (b) large and (c) small domains is also provided. The domain specific RMSDs are 0.6 Å and 0.4 Å, respectively.
Mentions: From the superposition of the apo and ligated LAOBP conformations (Fig. 3a), it is clear that there is pronounced conformational changes on ligand binding. In fact, the RMSD between the two LAOBP conformations is 3.5 Å. Similarly, the pairwise RMSD between the GBP pair is 4.0 Å. Although the RMSD values reported in Table 3 represent overall dissimilarity between pairs, this does not properly describe local similarities because members of the bPBP family are composed of two domains connected by a flexible linker that allows the protein to transition from apo and ligated conformations. SCOP does not discriminate between the two domains; nevertheless, common domain identification algorithms (i.e., PDP [40] and DomainParser [41,42]) do identify the two domains. In Table 2, the PDP domain boundaries are indicated. Note that the large domain is interrupted by insertion of the small one, resulting in two linkers across the domain boundary. The calculated pairwise RMSD between the large and small LAOBP domains individually is 0.4 Å and 0.6 Å, respectively (see Fig. 3b–c). (The corresponding RMSDs between the GBP domains are 0.6 Å and 0.8 Å.) These strong domain-specific similarities indicate that the large and small domains move more or less intact upon ligand binding, which is indicative of a hinge-like motion at the domain boundaries [43].

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