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High-Resolution Free-Energy Landscape Analysis of α-Helical Protein Folding: HP35 and Its Double Mutant.

Banushkina PV, Krivov SV - J Chem Theory Comput (2013)

Bottom Line: Natl.Four different estimations of the pre-exponential factor for both proteins give k 0 (-1) values of approximately a few tens of nanoseconds.Our analysis gives detailed information about folding of the proteins and can serve as a rigorous common language for extensive comparison between experiment and simulation.

View Article: PubMed Central - PubMed

Affiliation: Astbury Center for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds , Leeds LS2 9JT, United Kingdom.

ABSTRACT
The free-energy landscape can provide a quantitative description of folding dynamics, if determined as a function of an optimally chosen reaction coordinate. Here, we construct the optimal coordinate and the associated free-energy profile for all-helical proteins HP35 and its norleucine (Nle/Nle) double mutant, based on realistic equilibrium folding simulations [Piana et al. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 17845]. From the obtained profiles, we directly determine such basic properties of folding dynamics as the configurations of the minima and transition states (TS), the formation of secondary structure and hydrophobic core during the folding process, the value of the pre-exponential factor and its relation to the transition path times, the relation between the autocorrelation times in TS and minima. We also present an investigation of the accuracy of the pre-exponential factor estimation based on the transition-path times. Four different estimations of the pre-exponential factor for both proteins give k 0 (-1) values of approximately a few tens of nanoseconds. Our analysis gives detailed information about folding of the proteins and can serve as a rigorous common language for extensive comparison between experiment and simulation.

No MeSH data available.


Related in: MedlinePlus

(A) Hydrophobiccore formation during HP35 folding (the D statehas a fully disordered tertiary structure; in the I state, the firstand second helices formed but it still has an incomplete hydrophobiccore; the N state has a tightly packed hydrophobic core). (B) A native-likestructure with an incompletely folded hydrophobic core from the intermediatestate (single snapshot). (C) Contact formation between side-chainsTrp64 and Phe76 (the I state has contact between Trp64 and Phe76;the TS2 state shows the absence of Trp-Phe contact). The average configurationsare taken from Figure 1.
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fig4: (A) Hydrophobiccore formation during HP35 folding (the D statehas a fully disordered tertiary structure; in the I state, the firstand second helices formed but it still has an incomplete hydrophobiccore; the N state has a tightly packed hydrophobic core). (B) A native-likestructure with an incompletely folded hydrophobic core from the intermediatestate (single snapshot). (C) Contact formation between side-chainsTrp64 and Phe76 (the I state has contact between Trp64 and Phe76;the TS2 state shows the absence of Trp-Phe contact). The average configurationsare taken from Figure 1.

Mentions: Figure 4A explores the formation of the hydrophobic core (residues Phe47,Val50, Phe51, Phe58, and Leu69) during the folding process. The snapshotsshow that the formation of native topology and secondary structurebegins early during the folding process, while the stabilization ofthe hydrophobic core residues happens later. At the denatured state,unfolded protein has some helical content and a fully disordered tertiarystructure. The intermediate state is characterized by the first andsecond helices formed but an incomplete hydrophobic core. The redand yellow colors of side-chains Val50 and Leu69 indicate large fluctuationsof these residues. In the native state, the tightly packed hydrophobiccore is fully formed. This finding reproduces the experimental results37 and is in agreement with MD simulations, concludingthat secondary structure and topology develop earlier than the fullset of native contacts.32 Interestingly,the intermediate state contains conformations with a nearly nativesecondary structure and native-like topology (Figure 4B) but with an incompletely folded hydrophobic core.


High-Resolution Free-Energy Landscape Analysis of α-Helical Protein Folding: HP35 and Its Double Mutant.

Banushkina PV, Krivov SV - J Chem Theory Comput (2013)

(A) Hydrophobiccore formation during HP35 folding (the D statehas a fully disordered tertiary structure; in the I state, the firstand second helices formed but it still has an incomplete hydrophobiccore; the N state has a tightly packed hydrophobic core). (B) A native-likestructure with an incompletely folded hydrophobic core from the intermediatestate (single snapshot). (C) Contact formation between side-chainsTrp64 and Phe76 (the I state has contact between Trp64 and Phe76;the TS2 state shows the absence of Trp-Phe contact). The average configurationsare taken from Figure 1.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3860327&req=5

fig4: (A) Hydrophobiccore formation during HP35 folding (the D statehas a fully disordered tertiary structure; in the I state, the firstand second helices formed but it still has an incomplete hydrophobiccore; the N state has a tightly packed hydrophobic core). (B) A native-likestructure with an incompletely folded hydrophobic core from the intermediatestate (single snapshot). (C) Contact formation between side-chainsTrp64 and Phe76 (the I state has contact between Trp64 and Phe76;the TS2 state shows the absence of Trp-Phe contact). The average configurationsare taken from Figure 1.
Mentions: Figure 4A explores the formation of the hydrophobic core (residues Phe47,Val50, Phe51, Phe58, and Leu69) during the folding process. The snapshotsshow that the formation of native topology and secondary structurebegins early during the folding process, while the stabilization ofthe hydrophobic core residues happens later. At the denatured state,unfolded protein has some helical content and a fully disordered tertiarystructure. The intermediate state is characterized by the first andsecond helices formed but an incomplete hydrophobic core. The redand yellow colors of side-chains Val50 and Leu69 indicate large fluctuationsof these residues. In the native state, the tightly packed hydrophobiccore is fully formed. This finding reproduces the experimental results37 and is in agreement with MD simulations, concludingthat secondary structure and topology develop earlier than the fullset of native contacts.32 Interestingly,the intermediate state contains conformations with a nearly nativesecondary structure and native-like topology (Figure 4B) but with an incompletely folded hydrophobic core.

Bottom Line: Natl.Four different estimations of the pre-exponential factor for both proteins give k 0 (-1) values of approximately a few tens of nanoseconds.Our analysis gives detailed information about folding of the proteins and can serve as a rigorous common language for extensive comparison between experiment and simulation.

View Article: PubMed Central - PubMed

Affiliation: Astbury Center for Structural Molecular Biology, Faculty of Biological Sciences, University of Leeds , Leeds LS2 9JT, United Kingdom.

ABSTRACT
The free-energy landscape can provide a quantitative description of folding dynamics, if determined as a function of an optimally chosen reaction coordinate. Here, we construct the optimal coordinate and the associated free-energy profile for all-helical proteins HP35 and its norleucine (Nle/Nle) double mutant, based on realistic equilibrium folding simulations [Piana et al. Proc. Natl. Acad. Sci. U.S.A. 2012, 109, 17845]. From the obtained profiles, we directly determine such basic properties of folding dynamics as the configurations of the minima and transition states (TS), the formation of secondary structure and hydrophobic core during the folding process, the value of the pre-exponential factor and its relation to the transition path times, the relation between the autocorrelation times in TS and minima. We also present an investigation of the accuracy of the pre-exponential factor estimation based on the transition-path times. Four different estimations of the pre-exponential factor for both proteins give k 0 (-1) values of approximately a few tens of nanoseconds. Our analysis gives detailed information about folding of the proteins and can serve as a rigorous common language for extensive comparison between experiment and simulation.

No MeSH data available.


Related in: MedlinePlus