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Interactions between amino acid side chains in cylindrical hydrophobic nanopores with applications to peptide stability.

ABSTRACT: Confinement effects on protein stability are relevant in a number of biological applications ranging from encapsulation in the cylindrical cavity of a chaperonin, translocation through pores, and structure formation in the exit tunnel of the ribosome. Consequently, free energies of interaction between amino acid side chains in restricted spaces can provide insights into factors that control protein stability in nanopores. Using all-atom molecular dynamics simulations, we show that 3 pair interactions between side chains--hydrophobic (Ala-Phe), polar (Ser-Asn) and charged (Lys-Glu)--are substantially altered in hydrophobic, water-filled nanopores, relative to bulk water. When the pore holds water at bulk density, the hydrophobic pair is strongly destabilized and is driven to large separations corresponding to the width and the length of the cylindrical pore. As the water density is reduced, the preference of Ala and Phe to be at the boundary decreases, and the contact pair is preferred. A model that accounts for the volume accessible to Phe and Ala in the solvent-depleted region near the pore boundary explains the simulation results. In the pore, the hydrogen-bonded interactions between Ser and Asn have an enhanced dependence on their relative orientations, as compared with bulk water. When the side chains of Lys and Glu are restrained to be side by side, parallel to each other, then salt bridge formation is promoted in the nanopore. Based on these results, we argue and demonstrate that for a generic amphiphilic sequence, cylindrical confinement is likely to enhance thermodynamic stability relative to the bulk.

SUBMITTER: Vaitheeswaran S

PROVIDER: S-EPMC2584679 | biostudies-literature | 2008 Nov

REPOSITORIES: biostudies-literature

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Interactions between amino acid side chains in cylindrical hydrophobic nanopores with applications to peptide stability.

Vaitheeswaran S S Thirumalai D D

Proceedings of the National Academy of Sciences of the United States of America 20081112 46

Confinement effects on protein stability are relevant in a number of biological applications ranging from encapsulation in the cylindrical cavity of a chaperonin, translocation through pores, and structure formation in the exit tunnel of the ribosome. Consequently, free energies of interaction between amino acid side chains in restricted spaces can provide insights into factors that control protein stability in nanopores. Using all-atom molecular dynamics simulations, we show that 3 pair interac ...[more]

PMID: 19004772

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Project description:Amino acid side-chain conformational properties influence the overall structural and dynamic properties of proteins and, therefore, their biological functions. In this study, quantum mechanical (QM) potential energy surfaces for the rotation of side-chain χ(1) and χ(2) torsions in dipeptides in the alphaR, beta, and alphaL backbone conformations were calculated. The QM energy surfaces provide a broad view of the intrinsic conformational properties of each amino acid side-chain. The extent to which intrinsic energetics dictates side-chain orientation was studied through comparisons of the QM energy surfaces with χ(1) and χ(2) free energy surfaces from probability distributions obtained from a survey of high resolution crystal structures. In general, the survey probability maxima are centered in minima of the QM surfaces as expected for sp(3) (or sp(2) for χ(2) of Asn, Phe, Trp, and Tyr) atom centers with strong variations between amino acids occurring in the energies of the minima indicating intrinsic differences in rotamer preferences. High correlations between the QM and survey data were found for hydrophobic side-chains except Met, suggesting minimal influence of the protein and solution environments on their conformational distributions. Conversely, low correlations for polar or charged side-chains indicate a dominant role of the environment in stabilizing conformations that are not intrinsically favored. Data also link the presence of off-rotamers in His and Trp to favorable interactions with the backbone. Results also suggest that the intrinsic energetics of the side-chains of Phe and Tyr may play important roles in protein folding and stability. Analyses on whether intrinsic side-chain energetics can influence backbone preference identified a strong correlation for residues in the alphaL backbone conformation. It is suggested that this correlation reflects the intrinsic instability of the alphaL backbone such that assumption of this backbone conformation is facilitated by intrinsically favorable side-chain conformations. Together our results offer a broad overview of the conformational properties of amino acid side-chains and the QM data may be used as target data for force field optimization.

Dataset Information

Interactions between amino acid side chains in cylindrical hydrophobic nanopores with applications to peptide stability.

Publications

Interactions between amino acid side chains in cylindrical hydrophobic nanopores with applications to peptide stability.

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