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E9-Im9 colicin DNase-immunity protein biomolecular association in water: a multiple-copy and accelerated molecular dynamics simulation study.

Baron R, Wong SE, de Oliveira CA, McCammon JA - J Phys Chem B (2008)

Bottom Line: Im9 displays a significant reduction of backbone flexibility and a remarkable increase in motional correlation upon E9 association.E9-Im9 recognition involves shifts of conformational distributions, reorganization of intramolecular hydrogen bond patterns, and formation of new inter- and intramolecular interactions.The description of key transient biological interactions can be significantly enriched by the dynamic and atomic-level information provided by computer simulations.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, Department of Pharmacology, Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093-0365, USA. rbaron@mccammon.ucsd.edu

ABSTRACT
Protein-protein transient and dynamic interactions underlie all biological processes. The molecular dynamics (MD) of the E9 colicin DNase protein, its Im9 inhibitor protein, and their E9-Im9 recognition complex are investigated by combining multiple-copy (MC) MD and accelerated MD (aMD) explicit-solvent simulation approaches, after validation with crystalline-phase and solution experiments. Im9 shows higher flexibility than its E9 counterpart. Im9 displays a significant reduction of backbone flexibility and a remarkable increase in motional correlation upon E9 association. Im9 loops 23-31 and 54-64 open with respect to the E9-Im9 X-ray structure and show high conformational diversity. Upon association a large fraction (approximately 20 nm2) of E9 and Im9 protein surfaces become inaccessible to water. Numerous salt bridges transiently occurring throughout our six 50 ns long MC-MD simulations are not present in the X-ray model. Among these Im9 Glu31-E9 Arg96 and Im9 Glu41-Lys89 involve interface interactions. Through the use of 10 ns of Im9 aMD simulation, we reconcile the largest thermodynamic impact measured for Asp51Ala mutation with Im9 structure and dynamics. Lys57 acts as an essential molecular switch to shift Im9 surface loop towards an ideal configuration for E9 inhibition. This is achieved by switching Asp60-Lys57 and Asp62-Lys57 hydrogen bonds to Asp51-Lys57 salt bridge. E9-Im9 recognition involves shifts of conformational distributions, reorganization of intramolecular hydrogen bond patterns, and formation of new inter- and intramolecular interactions. The description of key transient biological interactions can be significantly enriched by the dynamic and atomic-level information provided by computer simulations.

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Conformational sampling of the Lys57−Asp51 salt bridge from key snapshots of the accelerated Im9_aMD simulation. Panel (a) shows Lys57 interacting with loop 54−64 residues when the salt bridge is not formed. Alternatively, the Lys57−Asp51 salt bridges can be formed when the 54−64 loop is (b) open or (c) closed. Panel (d) displays the corresponding quasi-canonical re-weighted normalized distribution of the salt-bridge distance.
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fig8: Conformational sampling of the Lys57−Asp51 salt bridge from key snapshots of the accelerated Im9_aMD simulation. Panel (a) shows Lys57 interacting with loop 54−64 residues when the salt bridge is not formed. Alternatively, the Lys57−Asp51 salt bridges can be formed when the 54−64 loop is (b) open or (c) closed. Panel (d) displays the corresponding quasi-canonical re-weighted normalized distribution of the salt-bridge distance.

Mentions: The preferred conformations of loop 54−64 are significantly dominated by the interactions formed by Lys57 within the loop region itself. From our MD simulations we observe loop configurations similar to the X-ray model (Figure 4). Additionally, loop dynamics events occurring on longer time scales can be observed on the basis of the Im9_aMD simulation (Figure 5). Our simulations reveal a larger number of key salt-bridge interactions than the X-ray model (Figure 7) also based on Im9_aMD (not shown). Lys57 forms transient hydrogen bonds to Asp60 and Asp62 throughout the Im9_aMD trajectory (Figure 8a). This corresponds to what observed from regular Im9_a and Im9_b simulations (Figure 4). Interestingly, Im9 displays also two alternative dominant configurations during the 10-ns aMD period, both characterized by a stable Asp51−Lys57 salt bridge (Figures 7 and 8b,c). In the first case, the 54−64 loop is open, in the second further closed than the X-ray model. The re-weighted normalized probability distribution of the Asp51:CG−Lys57:NZ distance confirms that the formation of this salt bridge, observed using aMD only, is also energetically stabilized (see largest peak at ∼0.35 nm, Figure 8d). Asp51Ala mutation prevents the Asp51−Lys57 salt-bridge anchoring of the 54−64 loop in its ideal configuration for E9 binding, with a consequent decrease of E9-Im9 binding free energy. We summarize this as a molecular switch that shifts Lys57 intraloop interactions to interactions with the more rigid helix III through a Asp51−Lys57 salt bridge.


E9-Im9 colicin DNase-immunity protein biomolecular association in water: a multiple-copy and accelerated molecular dynamics simulation study.

Baron R, Wong SE, de Oliveira CA, McCammon JA - J Phys Chem B (2008)

Conformational sampling of the Lys57−Asp51 salt bridge from key snapshots of the accelerated Im9_aMD simulation. Panel (a) shows Lys57 interacting with loop 54−64 residues when the salt bridge is not formed. Alternatively, the Lys57−Asp51 salt bridges can be formed when the 54−64 loop is (b) open or (c) closed. Panel (d) displays the corresponding quasi-canonical re-weighted normalized distribution of the salt-bridge distance.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2651752&req=5

fig8: Conformational sampling of the Lys57−Asp51 salt bridge from key snapshots of the accelerated Im9_aMD simulation. Panel (a) shows Lys57 interacting with loop 54−64 residues when the salt bridge is not formed. Alternatively, the Lys57−Asp51 salt bridges can be formed when the 54−64 loop is (b) open or (c) closed. Panel (d) displays the corresponding quasi-canonical re-weighted normalized distribution of the salt-bridge distance.
Mentions: The preferred conformations of loop 54−64 are significantly dominated by the interactions formed by Lys57 within the loop region itself. From our MD simulations we observe loop configurations similar to the X-ray model (Figure 4). Additionally, loop dynamics events occurring on longer time scales can be observed on the basis of the Im9_aMD simulation (Figure 5). Our simulations reveal a larger number of key salt-bridge interactions than the X-ray model (Figure 7) also based on Im9_aMD (not shown). Lys57 forms transient hydrogen bonds to Asp60 and Asp62 throughout the Im9_aMD trajectory (Figure 8a). This corresponds to what observed from regular Im9_a and Im9_b simulations (Figure 4). Interestingly, Im9 displays also two alternative dominant configurations during the 10-ns aMD period, both characterized by a stable Asp51−Lys57 salt bridge (Figures 7 and 8b,c). In the first case, the 54−64 loop is open, in the second further closed than the X-ray model. The re-weighted normalized probability distribution of the Asp51:CG−Lys57:NZ distance confirms that the formation of this salt bridge, observed using aMD only, is also energetically stabilized (see largest peak at ∼0.35 nm, Figure 8d). Asp51Ala mutation prevents the Asp51−Lys57 salt-bridge anchoring of the 54−64 loop in its ideal configuration for E9 binding, with a consequent decrease of E9-Im9 binding free energy. We summarize this as a molecular switch that shifts Lys57 intraloop interactions to interactions with the more rigid helix III through a Asp51−Lys57 salt bridge.

Bottom Line: Im9 displays a significant reduction of backbone flexibility and a remarkable increase in motional correlation upon E9 association.E9-Im9 recognition involves shifts of conformational distributions, reorganization of intramolecular hydrogen bond patterns, and formation of new inter- and intramolecular interactions.The description of key transient biological interactions can be significantly enriched by the dynamic and atomic-level information provided by computer simulations.

View Article: PubMed Central - PubMed

Affiliation: Department of Chemistry and Biochemistry, Center for Theoretical Biological Physics, Department of Pharmacology, Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093-0365, USA. rbaron@mccammon.ucsd.edu

ABSTRACT
Protein-protein transient and dynamic interactions underlie all biological processes. The molecular dynamics (MD) of the E9 colicin DNase protein, its Im9 inhibitor protein, and their E9-Im9 recognition complex are investigated by combining multiple-copy (MC) MD and accelerated MD (aMD) explicit-solvent simulation approaches, after validation with crystalline-phase and solution experiments. Im9 shows higher flexibility than its E9 counterpart. Im9 displays a significant reduction of backbone flexibility and a remarkable increase in motional correlation upon E9 association. Im9 loops 23-31 and 54-64 open with respect to the E9-Im9 X-ray structure and show high conformational diversity. Upon association a large fraction (approximately 20 nm2) of E9 and Im9 protein surfaces become inaccessible to water. Numerous salt bridges transiently occurring throughout our six 50 ns long MC-MD simulations are not present in the X-ray model. Among these Im9 Glu31-E9 Arg96 and Im9 Glu41-Lys89 involve interface interactions. Through the use of 10 ns of Im9 aMD simulation, we reconcile the largest thermodynamic impact measured for Asp51Ala mutation with Im9 structure and dynamics. Lys57 acts as an essential molecular switch to shift Im9 surface loop towards an ideal configuration for E9 inhibition. This is achieved by switching Asp60-Lys57 and Asp62-Lys57 hydrogen bonds to Asp51-Lys57 salt bridge. E9-Im9 recognition involves shifts of conformational distributions, reorganization of intramolecular hydrogen bond patterns, and formation of new inter- and intramolecular interactions. The description of key transient biological interactions can be significantly enriched by the dynamic and atomic-level information provided by computer simulations.

Show MeSH