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Allosteric transitions of supramolecular systems explored by network models: application to chaperonin GroEL.

Yang Z, Májek P, Bahar I - PLoS Comput. Biol. (2009)

Bottom Line: Coarse-grained models that lend themselves to analytical solutions appear to be the only possible means of approaching such cases.Application to bacterial chaperonin GroEL and comparisons with experimental data, results from action minimization algorithm, and previous simulations support the utility of aANM as a computationally efficient, yet physically plausible, tool for unraveling potential transition pathways sampled by large complexes/assemblies.An important outcome is the assessment of the critical inter-residue interactions formed/broken near the transition state(s), most of which involve conserved residues.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

ABSTRACT
Identification of pathways involved in the structural transitions of biomolecular systems is often complicated by the transient nature of the conformations visited across energy barriers and the multiplicity of paths accessible in the multidimensional energy landscape. This task becomes even more challenging in exploring molecular systems on the order of megadaltons. Coarse-grained models that lend themselves to analytical solutions appear to be the only possible means of approaching such cases. Motivated by the utility of elastic network models for describing the collective dynamics of biomolecular systems and by the growing theoretical and experimental evidence in support of the intrinsic accessibility of functional substates, we introduce a new method, adaptive anisotropic network model (aANM), for exploring functional transitions. Application to bacterial chaperonin GroEL and comparisons with experimental data, results from action minimization algorithm, and previous simulations support the utility of aANM as a computationally efficient, yet physically plausible, tool for unraveling potential transition pathways sampled by large complexes/assemblies. An important outcome is the assessment of the critical inter-residue interactions formed/broken near the transition state(s), most of which involve conserved residues.

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The cis ring inter-subunit interactions during                                the transition T→R″, based on the intact GroEL                                structure calculation.(A) Intersubunit interface near the intermediate domains (green) of                                two adjacent subunits in the cis ring. The                                backbones are shown in cartoon view and colored by domains: A                                (orange), I (green), and E (blue). Backbone atoms of three charged                                residues are shown by spheres. Positively and negatively charged                                residues are colored blue and red, respectively. (B) The                                inter-subunit hydrogen bond, E386-R197, in the T state of the                                    cis ring (1GR5). (C) During the transition to                                state R″/R, residue E386 in the I domain moves towards K80                                (blue sphere) in the E domain of the adjacent subunit, while R197 on                                the A domain moves away from E386. (D) The final configuration in                                the R″ state of the cis ring, represented                                by 1GRU. Residue E386 now forms a new hydrogen bond with K80.
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pcbi-1000360-g007: The cis ring inter-subunit interactions during the transition T→R″, based on the intact GroEL structure calculation.(A) Intersubunit interface near the intermediate domains (green) of two adjacent subunits in the cis ring. The backbones are shown in cartoon view and colored by domains: A (orange), I (green), and E (blue). Backbone atoms of three charged residues are shown by spheres. Positively and negatively charged residues are colored blue and red, respectively. (B) The inter-subunit hydrogen bond, E386-R197, in the T state of the cis ring (1GR5). (C) During the transition to state R″/R, residue E386 in the I domain moves towards K80 (blue sphere) in the E domain of the adjacent subunit, while R197 on the A domain moves away from E386. (D) The final configuration in the R″ state of the cis ring, represented by 1GRU. Residue E386 now forms a new hydrogen bond with K80.

Mentions: Experiments conducted with Arg197Ala mutant [67] pointed to the functional role of the salt bridge between E386 and R197 on adjacent subunits in the cis ring. This inter-subunit salt-bridge was also noted in early cryo-EM studies [68]. It forms in the T state of the ring (1GR5) (Figure 7A and 7B), and it has been proposed to be an essential component of the positive intra-ring cooperativity [69]. The R″ state of the same ring (1GRU) indicates, on the other hand, a new salt bridge, formed between E386 and K80 (on the E domain of the neighboring subunit) (Figure 7D). The aANM results shed light to the mechanism of this interchange of salt bridges. The separation between E386 and R197 α-carbons, originally equal to 15.7 Å (their charged ends being separated by 3.2 Å), gradually increases by the downwards motion of the intermediate domain. After 18 iterations (for T/T→R/T), the distance between E386 and R197 becomes larger than that between E386 and K80, and K80 replaces R197 to form a salt bridge with E386 (Figure 7C). Afterwards, R197 moves dramatically away from E386, led by the opening of the apical domain. Meanwhile the downward movement of helix M continues until the distance between the Cα-atoms of the new salt-bridge-forming residues E386 and K80 reduces to 8.6 Å.


Allosteric transitions of supramolecular systems explored by network models: application to chaperonin GroEL.

Yang Z, Májek P, Bahar I - PLoS Comput. Biol. (2009)

The cis ring inter-subunit interactions during                                the transition T→R″, based on the intact GroEL                                structure calculation.(A) Intersubunit interface near the intermediate domains (green) of                                two adjacent subunits in the cis ring. The                                backbones are shown in cartoon view and colored by domains: A                                (orange), I (green), and E (blue). Backbone atoms of three charged                                residues are shown by spheres. Positively and negatively charged                                residues are colored blue and red, respectively. (B) The                                inter-subunit hydrogen bond, E386-R197, in the T state of the                                    cis ring (1GR5). (C) During the transition to                                state R″/R, residue E386 in the I domain moves towards K80                                (blue sphere) in the E domain of the adjacent subunit, while R197 on                                the A domain moves away from E386. (D) The final configuration in                                the R″ state of the cis ring, represented                                by 1GRU. Residue E386 now forms a new hydrogen bond with K80.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2664929&req=5

pcbi-1000360-g007: The cis ring inter-subunit interactions during the transition T→R″, based on the intact GroEL structure calculation.(A) Intersubunit interface near the intermediate domains (green) of two adjacent subunits in the cis ring. The backbones are shown in cartoon view and colored by domains: A (orange), I (green), and E (blue). Backbone atoms of three charged residues are shown by spheres. Positively and negatively charged residues are colored blue and red, respectively. (B) The inter-subunit hydrogen bond, E386-R197, in the T state of the cis ring (1GR5). (C) During the transition to state R″/R, residue E386 in the I domain moves towards K80 (blue sphere) in the E domain of the adjacent subunit, while R197 on the A domain moves away from E386. (D) The final configuration in the R″ state of the cis ring, represented by 1GRU. Residue E386 now forms a new hydrogen bond with K80.
Mentions: Experiments conducted with Arg197Ala mutant [67] pointed to the functional role of the salt bridge between E386 and R197 on adjacent subunits in the cis ring. This inter-subunit salt-bridge was also noted in early cryo-EM studies [68]. It forms in the T state of the ring (1GR5) (Figure 7A and 7B), and it has been proposed to be an essential component of the positive intra-ring cooperativity [69]. The R″ state of the same ring (1GRU) indicates, on the other hand, a new salt bridge, formed between E386 and K80 (on the E domain of the neighboring subunit) (Figure 7D). The aANM results shed light to the mechanism of this interchange of salt bridges. The separation between E386 and R197 α-carbons, originally equal to 15.7 Å (their charged ends being separated by 3.2 Å), gradually increases by the downwards motion of the intermediate domain. After 18 iterations (for T/T→R/T), the distance between E386 and R197 becomes larger than that between E386 and K80, and K80 replaces R197 to form a salt bridge with E386 (Figure 7C). Afterwards, R197 moves dramatically away from E386, led by the opening of the apical domain. Meanwhile the downward movement of helix M continues until the distance between the Cα-atoms of the new salt-bridge-forming residues E386 and K80 reduces to 8.6 Å.

Bottom Line: Coarse-grained models that lend themselves to analytical solutions appear to be the only possible means of approaching such cases.Application to bacterial chaperonin GroEL and comparisons with experimental data, results from action minimization algorithm, and previous simulations support the utility of aANM as a computationally efficient, yet physically plausible, tool for unraveling potential transition pathways sampled by large complexes/assemblies.An important outcome is the assessment of the critical inter-residue interactions formed/broken near the transition state(s), most of which involve conserved residues.

View Article: PubMed Central - PubMed

Affiliation: Department of Computational Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.

ABSTRACT
Identification of pathways involved in the structural transitions of biomolecular systems is often complicated by the transient nature of the conformations visited across energy barriers and the multiplicity of paths accessible in the multidimensional energy landscape. This task becomes even more challenging in exploring molecular systems on the order of megadaltons. Coarse-grained models that lend themselves to analytical solutions appear to be the only possible means of approaching such cases. Motivated by the utility of elastic network models for describing the collective dynamics of biomolecular systems and by the growing theoretical and experimental evidence in support of the intrinsic accessibility of functional substates, we introduce a new method, adaptive anisotropic network model (aANM), for exploring functional transitions. Application to bacterial chaperonin GroEL and comparisons with experimental data, results from action minimization algorithm, and previous simulations support the utility of aANM as a computationally efficient, yet physically plausible, tool for unraveling potential transition pathways sampled by large complexes/assemblies. An important outcome is the assessment of the critical inter-residue interactions formed/broken near the transition state(s), most of which involve conserved residues.

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