Electronic polarization stabilizes tertiary structure prediction of HP-36

Abstract

Molecular dynamic (MD) simulations with both implicit and explicit solvent models have been carried out to study the folding dynamics of HP-36 protein. Starting from the extended conformation, the secondary structure of all three helices in HP-36 was formed in about 50 ns and remained stable in the remaining simulation. However, the formation of the tertiary structure was difficult. Although some intermediates were close to the native structure, the overall conformation was not stable. Further analysis revealed that the large structure fluctuation of loop and hydrophobic core regions was devoted mostly to the instability of the structure during MD simulation. The backbone root-mean-square deviation (RMSD) of the loop and hydrophobic core regions showed strong correlation with the backbone RMSD of the whole protein. The free energy landscape indicated that the distribution of main chain torsions in loop and turn regions was far away from the native state. Starting from an intermediate structure extracted from the initial AMBER simulation, HP-36 was found to generally fold to the native state under the dynamically adjusted polarized protein-specific charge (DPPC) simulation, while the peptide did not fold into the native structure when AMBER force filed was used. The two best folded structures were extracted and taken into further simulations in water employing AMBER03 charge and DPPC for 25 ns. Result showed that introducing polarization effect into interacting potential could stabilize the near-native protein structure.

Fig. 1

RMSDs of backbone atoms of the HP-36 from the native structure for the whole protein, helix 1, helix 2, and helix 3 as a function of MD simulation time using AMBER03 force field combined with the GB model. The embedded structure is the best folded structure with the lowest backbone RMSD

Fig. 2

RMSDs of backbone atoms of the HP-36 from the native structure for the whole protein, loop, and hydrophobic core, as a function of MD simulation time using AMBER03 force field and GB model. And the native structure (the left embedded structure) and the representative structure selected from the most populated cluster (the right embedded structure)

Fig. 3

Free energy contour maps as a function of these torsions of helix 1 (1) for ASP4 (A), GLU5 (B), ASP6 (C), PHE7 (D), LYS8 (E), of helix 2 (2) for ARG15 (A), SER16 (B), ALA17 (C), PHE18 (D), of helix 3 (3) for LEU23 (A), TRP24 (B), LYS25 (C), GLN26 (D), GLN27 (E), ASN28 (F), LEU29 (G), LYS30 (H) using AMBER03 force field and GB model. Black point denotes the value of corresponding torsion in native state

Fig. 3

Free energy contour maps as a function of these torsions of helix 1 (1) for ASP4 (A), GLU5 (B), ASP6 (C), PHE7 (D), LYS8 (E), of helix 2 (2) for ARG15 (A), SER16 (B), ALA17 (C), PHE18 (D), of helix 3 (3) for LEU23 (A), TRP24 (B), LYS25 (C), GLN26 (D), GLN27 (E), ASN28 (F), LEU29 (G), LYS30 (H) using AMBER03 force field and GB model. Black point denotes the value of corresponding torsion in native state

Fig. 3

Free energy contour maps as a function of these torsions of helix 1 (1) for ASP4 (A), GLU5 (B), ASP6 (C), PHE7 (D), LYS8 (E), of helix 2 (2) for ARG15 (A), SER16 (B), ALA17 (C), PHE18 (D), of helix 3 (3) for LEU23 (A), TRP24 (B), LYS25 (C), GLN26 (D), GLN27 (E), ASN28 (F), LEU29 (G), LYS30 (H) using AMBER03 force field and GB model. Black point denotes the value of corresponding torsion in native state

Fig. 4

Free energy contour maps as a function of these torsions of loop region for ALA9 (a), VAL10 (b), PHE11 (c), GLY12 (d), MET13(e) and THR14 (f), of turn region for ALA19 (g) and ASN20 (h) using AMBER03 force field and GB model. Black point denotes the value of corresponding torsion in native state

Fig. 5

a Backbone RMSD of HP-36 from the native structure along MD simulation starting from the intermediate structure (obtained from the implicit solvent simulation) using AMBER03 force field and DPPC combined with the GB model. b The intermediate structure and the final structure of MD simulation using AMBER and DPPC, respectively. c RMSD of backbone atoms of the peptide as a function of MD simulation time from two MD trajectories. The red curve denotes the trajectory discussed in the current paper and the black curve denotes another trajectory with the same starting structure but different random seed for momentum

Fig. 6

RMSDs of backbone atoms of the HP-36 from the native structure for the whole protein, helix 1, helix 2, and helix 3 as a function of MD simulation time using AMBER03 force field in explicit water model. The embedded structure is the best folded structure with the lowest backbone RMSD

Fig. 7

RMSDs of backbone atoms of the HP-36 from the native structure for the whole protein, loop and hydrophobic core, as a function of MD simulation time using AMBER03 force field in explicit water model. And the native structure (the left embedded structure) and the representative structure selected from the most populated cluster (the right embedded structure)

Fig. 8

Free energy contour maps as a function of these torsions of helix 1 (1) for ASP4 (A), GLU5 (B), ASP6 (C), PHE7 (D), LYS8 (E), of helix 2 (2) for ARG15 (A), SER16 (B), ALA17 (C), PHE18 (D), of helix 3 (3) for LEU23 (A), TRP24 (B), LYS25 (C), GLN26 (D), GLN27 (E), ASN28 (F), LEU29 (G), LYS30 (H) using AMBER03 force field and explicit water model. Black point denotes the value of corresponding torsion in native state

Fig. 8

Free energy contour maps as a function of these torsions of helix 1 (1) for ASP4 (A), GLU5 (B), ASP6 (C), PHE7 (D), LYS8 (E), of helix 2 (2) for ARG15 (A), SER16 (B), ALA17 (C), PHE18 (D), of helix 3 (3) for LEU23 (A), TRP24 (B), LYS25 (C), GLN26 (D), GLN27 (E), ASN28 (F), LEU29 (G), LYS30 (H) using AMBER03 force field and explicit water model. Black point denotes the value of corresponding torsion in native state

Fig. 8

Free energy contour maps as a function of these torsions of helix 1 (1) for ASP4 (A), GLU5 (B), ASP6 (C), PHE7 (D), LYS8 (E), of helix 2 (2) for ARG15 (A), SER16 (B), ALA17 (C), PHE18 (D), of helix 3 (3) for LEU23 (A), TRP24 (B), LYS25 (C), GLN26 (D), GLN27 (E), ASN28 (F), LEU29 (G), LYS30 (H) using AMBER03 force field and explicit water model. Black point denotes the value of corresponding torsion in native state

Fig. 9

Free energy contour maps as a function of these torsions of loop region for ALA9 (a), VAL10 (b), PHE11 (c), GLY12 (d), MET13(e) and THR14 (f), of turn region for ALA19 (g) and ASN20 (h) using AMBER03 force field and explicit water model. Black point denotes the value of correponding torsion in native state

Fig. 10

a Backbone RMSD of HP-36 from the best folded structure along MD simulation starting from the best folded structure shown in Fig. 1 using AMBER03 force field and DPPC in explicit water (simulation1). b The best folded structure and the final structure of MD simulation using AMBER and DPPC, respectively

Fig. 11

a Backbone RMSD of HP-36 from the best folded structure along MD simulation starting from the best folded structure shown in Fig. 6 using AMBER03 force field and DPPC in explicit water (simulation2). b The best folded structure and the final structure of MD simulation using AMBER and DPPC, respectively

Fig. 12

a RMSF of the protein starting from the best folded structure obtained using implicit model (simulation1) under AMBER and DPPC simulation b RMSF of the protein starting from the best folded structure obtained using explicit model (simulation2) under AMBER and DPPC simulation. Star denotes the value of loop and hydrophobic core regions

Fig. 13

a Comparison of the occupation percentage of H-bonds from simulation1 using AMBER and DPPC, respectively. b Comparison of the occupation percentage of H-bonds from simulation2 using AMBER and DPPC, respectively

Fig. 14

RMSD of backbone atoms of HP-36 from native structure as a function of MD simulation time using standard AMBER and PPC in explicit water model starting from the native state, respectively