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Reversible pH-controlled DNA-binding peptide nanotweezers: an in-silico study.

Sharma G, Rege K, Budil DE, Yarmush ML, Mavroidis C - Int J Nanomedicine (2008)

Bottom Line: Modulating the solution pH between neutral and acidic values results in the reversible movement of helices toward and away from each other and creates a complete closed-open-closed transition cycle between the helices.The efficacy of the mutant that demonstrated the most significant reversible actuation for environmentally responsive modulation of DNA-binding activity was also demonstrated.Our results have significant implications in bioseparations and in the engineering of novel transcription factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA.

ABSTRACT
We describe the molecular dynamics (MD)-aided engineering design of mutant peptides based on the alpha-helical coiled-coil GCN4 leucine zipper peptide (GCN4-p1) in order to obtain environmentally-responsive nanotweezers. The actuation mechanism of the nanotweezers depends on the modification of electrostatic charges on the residues along the length of the coiled coil. Modulating the solution pH between neutral and acidic values results in the reversible movement of helices toward and away from each other and creates a complete closed-open-closed transition cycle between the helices. Our results indicate that the mutants show a reversible opening of up to 15 A (1.5 nm; approximately 150% of the initial separation) upon pH actuation. Investigation on the physicochemical phenomena that influence conformational properties, structural stability, and reversibility of the coiled-coil peptide-based nanotweezers revealed that a rationale- and design-based approach is needed to engineer stable peptide or macromolecules into stimuli-responsive devices. The efficacy of the mutant that demonstrated the most significant reversible actuation for environmentally responsive modulation of DNA-binding activity was also demonstrated. Our results have significant implications in bioseparations and in the engineering of novel transcription factors.

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System for studying the DNA-binding modulation of the molecular                    nanotweezer.
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f3-ijn-3-505: System for studying the DNA-binding modulation of the molecular nanotweezer.

Mentions: where U is the potential energy, k is spring constant, v is the pulling velocity, t is time, r is the actual position of the pulling atom, r0 is the initial position of the pulling atom, and n is the pulling direction. A harmonic spring of stiffness, k = 0.2 kcal/mol/Å2, was used and the DNA molecule was pulled along the longitudinal axis of the GCN4 peptide with a constant velocity v = 10 Å/ns (Figure 3). At low pH, the N1 atom of A nucleoside (pKa~3.8) and N atom of C nucleoside (pKa~4.5) are know to accept a proton, thereby neutralizing the charge on the entire nucleotide (Saenger 1984). At moderate pH (3–5) range only a fraction of the A and C nucleosides can be expected to be protonated. We therefore chose to protonate all of A nucleosides which could effectively correspond to a simulation carried out at pH 4 (Heng et al 2006). Partial charges for the N1-protonated A nucleoside were used as reported in (Heng et al 2006) and were kindly provided by Dr. Aleksei Aksimentiev. The entire GCN4–DNA system was solvated in a water box and neutralized using NaCl salt at 20 mM concentration. All the other simulation parameters are the same as described previously.


Reversible pH-controlled DNA-binding peptide nanotweezers: an in-silico study.

Sharma G, Rege K, Budil DE, Yarmush ML, Mavroidis C - Int J Nanomedicine (2008)

System for studying the DNA-binding modulation of the molecular                    nanotweezer.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2636583&req=5

f3-ijn-3-505: System for studying the DNA-binding modulation of the molecular nanotweezer.
Mentions: where U is the potential energy, k is spring constant, v is the pulling velocity, t is time, r is the actual position of the pulling atom, r0 is the initial position of the pulling atom, and n is the pulling direction. A harmonic spring of stiffness, k = 0.2 kcal/mol/Å2, was used and the DNA molecule was pulled along the longitudinal axis of the GCN4 peptide with a constant velocity v = 10 Å/ns (Figure 3). At low pH, the N1 atom of A nucleoside (pKa~3.8) and N atom of C nucleoside (pKa~4.5) are know to accept a proton, thereby neutralizing the charge on the entire nucleotide (Saenger 1984). At moderate pH (3–5) range only a fraction of the A and C nucleosides can be expected to be protonated. We therefore chose to protonate all of A nucleosides which could effectively correspond to a simulation carried out at pH 4 (Heng et al 2006). Partial charges for the N1-protonated A nucleoside were used as reported in (Heng et al 2006) and were kindly provided by Dr. Aleksei Aksimentiev. The entire GCN4–DNA system was solvated in a water box and neutralized using NaCl salt at 20 mM concentration. All the other simulation parameters are the same as described previously.

Bottom Line: Modulating the solution pH between neutral and acidic values results in the reversible movement of helices toward and away from each other and creates a complete closed-open-closed transition cycle between the helices.The efficacy of the mutant that demonstrated the most significant reversible actuation for environmentally responsive modulation of DNA-binding activity was also demonstrated.Our results have significant implications in bioseparations and in the engineering of novel transcription factors.

View Article: PubMed Central - PubMed

Affiliation: Department of Mechanical and Industrial Engineering, Northeastern University, Boston, MA 02115, USA.

ABSTRACT
We describe the molecular dynamics (MD)-aided engineering design of mutant peptides based on the alpha-helical coiled-coil GCN4 leucine zipper peptide (GCN4-p1) in order to obtain environmentally-responsive nanotweezers. The actuation mechanism of the nanotweezers depends on the modification of electrostatic charges on the residues along the length of the coiled coil. Modulating the solution pH between neutral and acidic values results in the reversible movement of helices toward and away from each other and creates a complete closed-open-closed transition cycle between the helices. Our results indicate that the mutants show a reversible opening of up to 15 A (1.5 nm; approximately 150% of the initial separation) upon pH actuation. Investigation on the physicochemical phenomena that influence conformational properties, structural stability, and reversibility of the coiled-coil peptide-based nanotweezers revealed that a rationale- and design-based approach is needed to engineer stable peptide or macromolecules into stimuli-responsive devices. The efficacy of the mutant that demonstrated the most significant reversible actuation for environmentally responsive modulation of DNA-binding activity was also demonstrated. Our results have significant implications in bioseparations and in the engineering of novel transcription factors.

Show MeSH
Related in: MedlinePlus