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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 Im9 23−31 and 54−64 loops from key snapshots of the accelerated Im9_aMD simulation (grey cartoon) and corresponding model from E9-Im9 crystal X-ray diffraction experiments (cyan cartoon). The two loops are shown when (a) both open, (b) both closed, and (c) close to the X-ray model configuration. Panel (d) shows an example with 23−31 loop open while 54−64 loop closed. See Table 1 for Im9_aMD simulation set-up and  for computational details.
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fig5: Conformational sampling of Im9 23−31 and 54−64 loops from key snapshots of the accelerated Im9_aMD simulation (grey cartoon) and corresponding model from E9-Im9 crystal X-ray diffraction experiments (cyan cartoon). The two loops are shown when (a) both open, (b) both closed, and (c) close to the X-ray model configuration. Panel (d) shows an example with 23−31 loop open while 54−64 loop closed. See Table 1 for Im9_aMD simulation set-up and for computational details.

Mentions: Figure 5 summarizes Im9 dynamics from snapshots of our 10 ns long aMD simulation. Im9 loops 23−31 and 54−64 significantly open with respect to the E9-Im9 X-ray structure model(8) (Figure 5a). Both loops can also transiently twist farther apart than observed in the crystal (Figure 5b). Yet, repeatedly the aMD simulation visits configurations close to the X-ray model (Figure 5c). This demonstrates that the dynamic behavior observed in our explicit solvent simulations is consistent with the ensemble-averaged E9-Im9 crystal X-ray model. Interestingly, the motion of 23−31 and 54−64 loops is not strictly correlated, and alternatively one only of the two loops display larger mobility (see example snapshot in Figure 5d).


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 Im9 23−31 and 54−64 loops from key snapshots of the accelerated Im9_aMD simulation (grey cartoon) and corresponding model from E9-Im9 crystal X-ray diffraction experiments (cyan cartoon). The two loops are shown when (a) both open, (b) both closed, and (c) close to the X-ray model configuration. Panel (d) shows an example with 23−31 loop open while 54−64 loop closed. See Table 1 for Im9_aMD simulation set-up and  for computational details.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

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

fig5: Conformational sampling of Im9 23−31 and 54−64 loops from key snapshots of the accelerated Im9_aMD simulation (grey cartoon) and corresponding model from E9-Im9 crystal X-ray diffraction experiments (cyan cartoon). The two loops are shown when (a) both open, (b) both closed, and (c) close to the X-ray model configuration. Panel (d) shows an example with 23−31 loop open while 54−64 loop closed. See Table 1 for Im9_aMD simulation set-up and for computational details.
Mentions: Figure 5 summarizes Im9 dynamics from snapshots of our 10 ns long aMD simulation. Im9 loops 23−31 and 54−64 significantly open with respect to the E9-Im9 X-ray structure model(8) (Figure 5a). Both loops can also transiently twist farther apart than observed in the crystal (Figure 5b). Yet, repeatedly the aMD simulation visits configurations close to the X-ray model (Figure 5c). This demonstrates that the dynamic behavior observed in our explicit solvent simulations is consistent with the ensemble-averaged E9-Im9 crystal X-ray model. Interestingly, the motion of 23−31 and 54−64 loops is not strictly correlated, and alternatively one only of the two loops display larger mobility (see example snapshot in Figure 5d).

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