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Computing the relative stabilities and the per-residue components in protein conformational changes.

ABSTRACT: Protein molecules often undergo conformational changes. In order to gain insights into the forces that drive such changes, it would be useful to have a method that computes the per-residue contributions to the conversion free energy. Here, we describe the "confine-convert-release" (CCR) method, which is applicable to large conformational changes. We show that CCR correctly predicts the stable states of several "chameleon" sequences that have previously been challenging for molecular simulations. CCR can often discriminate better from worse predictions of native protein models in critical assessment of protein structure prediction (CASP). We show how the total conversion free energies can be parsed into per-residue free-energy components. Such parsing gives insights into which amino acids are most responsible for given transformations. For example, here we are able to "reverse-engineer" the known design principles of the chameleon proteins. This opens up the possibility for systematic improvements in structure-prediction scoring functions, in the design of protein conformational switches, and in interpreting protein mechanisms at the amino-acid level.

SUBMITTER: Roy A

PROVIDER: S-EPMC3905753 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Computing the relative stabilities and the per-residue components in protein conformational changes.

Roy Arijit A Roy Arijit A Perez Alberto A Dill Ken A KA Maccallum Justin L JL

Structure (London, England : 1993) 20131205 1

Protein molecules often undergo conformational changes. In order to gain insights into the forces that drive such changes, it would be useful to have a method that computes the per-residue contributions to the conversion free energy. Here, we describe the "confine-convert-release" (CCR) method, which is applicable to large conformational changes. We show that CCR correctly predicts the stable states of several "chameleon" sequences that have previously been challenging for molecular simulations. ...[more]

PMID: 24316402

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Project description:We have previously studied the unfolding equilibrium of bacterioopsin in a single phase solvent, using Förster mechanism fluorescence resonance energy transfer (FRET) as a probe, from tryptophan donors to a dansyl acceptor. We observed an apparent unfolding transition in bacterioopsin perturbed by increasing ethanol concentrations [Nannepaga et al. (2004) Biochemistry 43, 50-59]. We have further investigated this transition and find that the unfolding is pH-dependent. We have now measured the apparent pK of acid-induced unfolding of bacterioopsin in 90% ethanol. When the acceptor is on helix B (Lys 41), the apparent pK for unfolding is 4.75; on the EF connecting loop (Cys 163), 5.15; and on helix G (Cys 222), 5.75. Five-helix proteolytic fragments are less stable. The apparent unfolding pKs are 5.46 for residues 72-248 (Cys 163) and 7.36 for residues 1-166 (Lys 41). When interpreted in terms of a simple equilibrium model for unfolding, the apparent pKs give relative free energies of unfolding in the range of -0.54 to -3.5 kcal/mol. The results suggest that the C-terminal helix of bacterioopsin is less stably folded than the N-terminal helices. We analyzed the pairwise helix-helix interaction surfaces of bacteriorhodopsin and three other seven-transmembrane-helix proteins on the basis of crystal structures. The results show that the interaction surfaces are smoother and the helix axis separations are closer in the amino-terminal two-thirds of the proteins compared with the carboxyl-terminal one-third. However, the F helix is important in stabilizing the folded structure, as shown by the instability of the 1-166 fragment. Considering the high-resolution crystal structure of bacteriorhodopsin, there are no obvious helix-helix interactions involving protein side chains which would be destabilized by protonation at the estimated pH of the unfolding transitions. However, a number of helix-bridging water molecules could become protonated, thereby weakening the helix-helix interactions.

Dataset Information

Computing the relative stabilities and the per-residue components in protein conformational changes.

Publications

Computing the relative stabilities and the per-residue components in protein conformational changes.

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