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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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Time series of backbone (a) root-mean-square deviation, RMSD, from the X-ray structure of the E9-Im9 complex and (b) radius of gyration, RGYR, for MC-MD simulations Im9_a (black), Im9_b (red), E9_a (green), E9_b (blue), E9-Im9_a (orange), and E9-Im9_b (brown). All Cα-atoms excluding first five and last five residues were used. See Table 1 for reference codes and Methods for computational details.
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fig1: Time series of backbone (a) root-mean-square deviation, RMSD, from the X-ray structure of the E9-Im9 complex and (b) radius of gyration, RGYR, for MC-MD simulations Im9_a (black), Im9_b (red), E9_a (green), E9_b (blue), E9-Im9_a (orange), and E9-Im9_b (brown). All Cα-atoms excluding first five and last five residues were used. See Table 1 for reference codes and Methods for computational details.

Mentions: Figure 1a shows the backbone Cα atom-positional root-mean-square deviation (RMSD) between the trajectory structures and the corresponding X-ray structure of the E9-Im9 complex.(8) These fluctuations are of small magnitude overall and remain stable along the simulation time (standard deviations for E9-Im9_a, 0.01; E9-Im9_b, 0.01; E9_a, 0.01; E9_b, 0.01 nm). Im9 fluctuations are comparatively larger (standard deviations for Im9_a and Im9_b: 0.03 and 0.05 nm) and demonstrate higher structural deviations for unbound Im9 in the liquid phase. Most of the conformational diversity observed in Im9 dynamics can be attributed to the high flexibility of its 54−64 loop (Supporting Information, Figure S1).


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)

Time series of backbone (a) root-mean-square deviation, RMSD, from the X-ray structure of the E9-Im9 complex and (b) radius of gyration, RGYR, for MC-MD simulations Im9_a (black), Im9_b (red), E9_a (green), E9_b (blue), E9-Im9_a (orange), and E9-Im9_b (brown). All Cα-atoms excluding first five and last five residues were used. See Table 1 for reference codes and Methods for computational details.
© Copyright Policy - open-access - ccc-price
Related In: Results  -  Collection

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

fig1: Time series of backbone (a) root-mean-square deviation, RMSD, from the X-ray structure of the E9-Im9 complex and (b) radius of gyration, RGYR, for MC-MD simulations Im9_a (black), Im9_b (red), E9_a (green), E9_b (blue), E9-Im9_a (orange), and E9-Im9_b (brown). All Cα-atoms excluding first five and last five residues were used. See Table 1 for reference codes and Methods for computational details.
Mentions: Figure 1a shows the backbone Cα atom-positional root-mean-square deviation (RMSD) between the trajectory structures and the corresponding X-ray structure of the E9-Im9 complex.(8) These fluctuations are of small magnitude overall and remain stable along the simulation time (standard deviations for E9-Im9_a, 0.01; E9-Im9_b, 0.01; E9_a, 0.01; E9_b, 0.01 nm). Im9 fluctuations are comparatively larger (standard deviations for Im9_a and Im9_b: 0.03 and 0.05 nm) and demonstrate higher structural deviations for unbound Im9 in the liquid phase. Most of the conformational diversity observed in Im9 dynamics can be attributed to the high flexibility of its 54−64 loop (Supporting Information, Figure S1).

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