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A free-energy approach for all-atom protein simulation.

ABSTRACT: All-atom free-energy methods offer a promising alternative to kinetic molecular mechanics simulations of protein folding and association. Here we report an accurate, transferable all-atom biophysical force field (PFF02) that stabilizes the native conformation of a wide range of proteins as the global optimum of the free-energy landscape. For 32 proteins of the ROSETTA decoy set and six proteins that we have previously folded with PFF01, we find near-native conformations with an average backbone RMSD of 2.14 A to the native conformation and an average Z-score of -3.46 to the corresponding decoy set. We used nonequilibrium sampling techniques starting from completely extended conformations to exhaustively sample the energy surface of three nonhomologous hairpin-peptides, a three-stranded beta-sheet, the all-helical 40 amino-acid HIV accessory protein, and a zinc-finger beta beta alpha motif, and find near-native conformations for the minimal energy for each protein. Using a massively parallel evolutionary algorithm, we also obtain a near-native low-energy conformation for the 54 amino-acid engrailed homeodomain. Our force field thus stabilized near-native conformations for a total of 20 proteins of all structure classes with an average RMSD of only 3.06 A to their respective experimental conformations.

SUBMITTER: Verma A

PROVIDER: S-EPMC2711412 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

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A free-energy approach for all-atom protein simulation.

Verma Abhinav A Wenzel Wolfgang W

Biophysical journal 20090501 9

All-atom free-energy methods offer a promising alternative to kinetic molecular mechanics simulations of protein folding and association. Here we report an accurate, transferable all-atom biophysical force field (PFF02) that stabilizes the native conformation of a wide range of proteins as the global optimum of the free-energy landscape. For 32 proteins of the ROSETTA decoy set and six proteins that we have previously folded with PFF01, we find near-native conformations with an average backbone ...[more]

PMID: 19413955

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Project description:Using a recently developed binary bilayer system (BBS) consisting of two patches of laterally contacting bilayers, umbrella sampling molecular dynamics (MD) simulations were performed for quantitative characterization of protein-lipid interactions. The BBS is composed of 1,2-dilauroyl-sn-glycero-3-phosphocholine (DLPC) and 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) with an embedded model membrane protein, a gramicidin A (gA) channel. The calculated free energy difference for the transfer of a gA channel from DLPC (hydrophobic thickness ? 21.5 Å) to DMPC (hydrophobic thickness ? 25.5 Å) bilayers, ?G(DLPC ? DMPC), is -2.2 ± 0.7 kcal/mol. This value appears at odds with the traditional view that the hydrophobic length of the gA channel is ?22 Å. To understand this discrepancy, we first note that recent MD simulations by different groups have shown that lipid bilayer thickness profiles in the vicinity of a gA channel differ qualitatively from the deformation profile predicted from continuum elastic bilayer models. Our MD simulations at low and high gA:lipid molar ratios and different membrane compositions indicate that the gA channel's effective hydrophobic length is ?26 Å. Using this effective hydrophobic length, ?G(DLPC ? DMPC) determined here is in excellent agreement with predictions based on continuum elastic models (-3.0 to -2.2 kcal/mol) where the bilayer deformation energy is approximated as a harmonic function of the mismatch between the channel's effective hydrophobic length and the hydrophobic thickness of the bilayer. The free energy profile for gA in the BBS includes a barrier at the interface between the two bilayers which can be attributed to the line tension at the interface between two bilayers with different hydrophobic thicknesses. This observation implies that translation of a peptide between two different regions of a cell membrane (such as between the liquid ordered and disordered phases) may include effects of a barrier at the interface in addition to the relative free energies of the species far from the interface. The BBS allows for direct transfer free energy calculations between bilayers without a need of a reference medium, such as bulk water, and thus provides an efficient simulation protocol for the quantitative characterization of protein-lipid interactions at all-atom resolution.

Project description:RNA hairpin loops are one of the most abundant secondary structure elements and participate in RNA folding and protein-RNA recognition. To characterize the free energy surface of RNA hairpin folding at an atomic level, we calculated the potential of mean force (PMF) as a function of the end-to-end distance, by using umbrella sampling simulations in explicit solvent. Two RNA hairpins containing tetraloop cUUCGg and cUUUUg are studied with AMBER ff99 and CHARMM27 force fields. Experimentally, the UUCG hairpin is known to be significantly more stable than UUUU. In this study, the calculations using AMBER force field give a qualitatively correct description for the folding of two RNA hairpins, as the calculated PMF confirms the global stability of the folded structures and the resulting relative folding free energy is in quantitative agreement with the experimental result. The hairpin stabilities are also correctly differentiated by the more rapid molecular mechanics-Poisson Boltzmann-surface area approach, but the relative free energy estimated from this method is overestimated. The free energy profile shows that the native state basin and the unfolded state plateau are separated by a wide shoulder region, which samples a variety of native-like structures with frayed terminal basepair. The calculated PMF lacks major barriers that are expected near the transition regions, and this is attributed to the limitation of the 1-D reaction coordinate. The PMF results are compared with other studies of small RNA hairpins using kinetics method and coarse grained models. The two RNA hairpins described by CHARMM27 are significantly more deformable than those represented by AMBER. Compared with the AMBER results, the CHARMM27 calculated DeltaG(fold) for the UUUU tetraloop is in better agreement with the experimental results. However, the CHARMM27 calculation does not confirm the global stability of the experimental UUCG structure; instead, the extended conformations are predicted to be thermodynamically stable in solution. This finding is further supported by separate unrestrained CHARMM27 simulations, in which the UUCG hairpin unfolds spontaneously within 10 ns. The instability of the UUCG hairpin originates from the loop region, and propagates to the stem. The results of this study provide a molecular picture of RNA hairpin unfolding and reveal problems in the force field descriptions for the conformational energy of certain RNA hairpin.

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A free-energy approach for all-atom protein simulation.

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A free-energy approach for all-atom protein simulation.

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