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Role of tryptophan side chain dynamics on the Trp-cage mini-protein folding studied by molecular dynamics simulations.

Kannan S, Zacharias M - PLoS ONE (2014)

Bottom Line: Whereas the majority of intermediate start structures with the central Trp side chain in a near-native rotameric state folded successfully within less than 100 ns only a fraction of start structures reached near-native folded states with an initially non-native Trp side chain rotamer state.Weak restraining of the Trp side chain dihedral angles to the state in the folded protein resulted in significant acceleration of the folding both starting from fully extended or intermediate conformations.The results indicate that the side chain conformation of the central Trp residue can create a significant barrier for controlling transitions to a near native folded structure.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Institute, Agency for Science Technology and Research, Singapore, Singapore ; Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore, Singapore.

ABSTRACT
The 20 residue Trp-cage mini-protein is one of smallest proteins that adopt a stable folded structure containing also well-defined secondary structure elements. The hydrophobic core is arranged around a single central Trp residue. Despite several experimental and simulation studies the detailed folding mechanism of the Trp-cage protein is still not completely understood. Starting from fully extended as well as from partially folded Trp-cage structures a series of molecular dynamics simulations in explicit solvent and using four different force fields was performed. All simulations resulted in rapid collapse of the protein to on average relatively compact states. The simulations indicate a significant dependence of the speed of folding to near-native states on the side chain rotamer state of the central Trp residue. Whereas the majority of intermediate start structures with the central Trp side chain in a near-native rotameric state folded successfully within less than 100 ns only a fraction of start structures reached near-native folded states with an initially non-native Trp side chain rotamer state. Weak restraining of the Trp side chain dihedral angles to the state in the folded protein resulted in significant acceleration of the folding both starting from fully extended or intermediate conformations. The results indicate that the side chain conformation of the central Trp residue can create a significant barrier for controlling transitions to a near native folded structure. Similar mechanisms might be of importance for the folding of other protein structures.

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Related in: MedlinePlus

Free and restrained MD simulations of intermediate Trp-cage structure.RMSDCα with respect to the native Trp-cage structure starting from an intermediate state (of set 2) with (red lines) and without (black lines) side chain dihedral angle restraints on Trp6 residue vs. simulation time. Results are shown for three different force fields (A) ff03, (B) ff99SB and (C) ff99SB_NMR.
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pone-0088383-g008: Free and restrained MD simulations of intermediate Trp-cage structure.RMSDCα with respect to the native Trp-cage structure starting from an intermediate state (of set 2) with (red lines) and without (black lines) side chain dihedral angle restraints on Trp6 residue vs. simulation time. Results are shown for three different force fields (A) ff03, (B) ff99SB and (C) ff99SB_NMR.

Mentions: In order to further check the importance of the Trp6 rotameric state for the speed of the final Trp-cage folding, simulations in the presence of side chain dihedral restraints of the Trp6 to keep it close to the native rotameric state were performed starting from a set 2 start structure that didn’t reach the folded state within 100 ns time (similar to the simulations starting from extended structures, see above). As a result of dihedral angle restraints, the set 2 starting structures folded successfully to near-native structures within 100 ns, while the same structures didn’t reach the correctly folded state during 100 ns unrestrained simulation (compare red and black RMSDCα curves in Figure 8 and summarized results in Table 2).


Role of tryptophan side chain dynamics on the Trp-cage mini-protein folding studied by molecular dynamics simulations.

Kannan S, Zacharias M - PLoS ONE (2014)

Free and restrained MD simulations of intermediate Trp-cage structure.RMSDCα with respect to the native Trp-cage structure starting from an intermediate state (of set 2) with (red lines) and without (black lines) side chain dihedral angle restraints on Trp6 residue vs. simulation time. Results are shown for three different force fields (A) ff03, (B) ff99SB and (C) ff99SB_NMR.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3921895&req=5

pone-0088383-g008: Free and restrained MD simulations of intermediate Trp-cage structure.RMSDCα with respect to the native Trp-cage structure starting from an intermediate state (of set 2) with (red lines) and without (black lines) side chain dihedral angle restraints on Trp6 residue vs. simulation time. Results are shown for three different force fields (A) ff03, (B) ff99SB and (C) ff99SB_NMR.
Mentions: In order to further check the importance of the Trp6 rotameric state for the speed of the final Trp-cage folding, simulations in the presence of side chain dihedral restraints of the Trp6 to keep it close to the native rotameric state were performed starting from a set 2 start structure that didn’t reach the folded state within 100 ns time (similar to the simulations starting from extended structures, see above). As a result of dihedral angle restraints, the set 2 starting structures folded successfully to near-native structures within 100 ns, while the same structures didn’t reach the correctly folded state during 100 ns unrestrained simulation (compare red and black RMSDCα curves in Figure 8 and summarized results in Table 2).

Bottom Line: Whereas the majority of intermediate start structures with the central Trp side chain in a near-native rotameric state folded successfully within less than 100 ns only a fraction of start structures reached near-native folded states with an initially non-native Trp side chain rotamer state.Weak restraining of the Trp side chain dihedral angles to the state in the folded protein resulted in significant acceleration of the folding both starting from fully extended or intermediate conformations.The results indicate that the side chain conformation of the central Trp residue can create a significant barrier for controlling transitions to a near native folded structure.

View Article: PubMed Central - PubMed

Affiliation: Bioinformatics Institute, Agency for Science Technology and Research, Singapore, Singapore ; Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore, Singapore.

ABSTRACT
The 20 residue Trp-cage mini-protein is one of smallest proteins that adopt a stable folded structure containing also well-defined secondary structure elements. The hydrophobic core is arranged around a single central Trp residue. Despite several experimental and simulation studies the detailed folding mechanism of the Trp-cage protein is still not completely understood. Starting from fully extended as well as from partially folded Trp-cage structures a series of molecular dynamics simulations in explicit solvent and using four different force fields was performed. All simulations resulted in rapid collapse of the protein to on average relatively compact states. The simulations indicate a significant dependence of the speed of folding to near-native states on the side chain rotamer state of the central Trp residue. Whereas the majority of intermediate start structures with the central Trp side chain in a near-native rotameric state folded successfully within less than 100 ns only a fraction of start structures reached near-native folded states with an initially non-native Trp side chain rotamer state. Weak restraining of the Trp side chain dihedral angles to the state in the folded protein resulted in significant acceleration of the folding both starting from fully extended or intermediate conformations. The results indicate that the side chain conformation of the central Trp residue can create a significant barrier for controlling transitions to a near native folded structure. Similar mechanisms might be of importance for the folding of other protein structures.

Show MeSH
Related in: MedlinePlus