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A coarse-grained alpha-carbon protein model with anisotropic hydrogen-bonding.

ABSTRACT: We develop a sequence based alpha-carbon model to incorporate a mean field estimate of the orientation dependence of the polypeptide chain that gives rise to specific hydrogen bond pairing to stabilize alpha-helices and beta-sheets. We illustrate the success of the new protein model in capturing thermodynamic measures and folding mechanism of proteins L and G. Compared to our previous coarse-grained model, the new model shows greater folding cooperativity and improvements in designability of protein sequences, as well as predicting correct trends for kinetic rates and mechanism for proteins L and G. We believe the model is broadly applicable to other protein folding and protein-protein co-assembly processes, and does not require experimental input beyond the topology description of the native state. Even without tertiary topology information, it can also serve as a mid-resolution protein model for more exhaustive conformational search strategies that can bridge back down to atomic descriptions of the polypeptide chain.

SUBMITTER: Yap EH

PROVIDER: S-EPMC3474853 | biostudies-literature | 2008 Feb

REPOSITORIES: biostudies-literature

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A coarse-grained alpha-carbon protein model with anisotropic hydrogen-bonding.

Yap Eng-Hui EH Fawzi Nicolas Lux NL Head-Gordon Teresa T

Proteins 20080201 3

We develop a sequence based alpha-carbon model to incorporate a mean field estimate of the orientation dependence of the polypeptide chain that gives rise to specific hydrogen bond pairing to stabilize alpha-helices and beta-sheets. We illustrate the success of the new protein model in capturing thermodynamic measures and folding mechanism of proteins L and G. Compared to our previous coarse-grained model, the new model shows greater folding cooperativity and improvements in designability of pro ...[more]

PMID: 17879350

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Project description:Reversible protein cluster formation is an important initial step in the processes of native and non-native protein aggregation, but involves relatively long time and length scales for detailed atomistic simulations and extensive mapping of free energy landscapes. A coarse-grained (CG) model is presented to semiquantitatively characterize the thermodynamics and key configurations involved in the landscape for protein oligomerization, as well as experimental measures of interactions such as the osmotic second virial coefficient (B22). Based on earlier work (Grüenberger et al., J. Phys. Chem. B 2013, 117, 763), this CG model treats proteins as rigid bodies composed of one bead per amino acid, with each amino acid having specific parameters for its size, hydrophobicity, and charge. The net interactions are a combination of steric repulsions, short-range attractions, and screened long-range charge-charge interactions. Model parametrization was done by fitting simulation results against experimental value of B22 as a function of solution ionic strength for ?-chymotrypsinogen A and ?D-Crystallin (gD-Crys). The CG model is applied to characterize the pairwise interactions and dimerization of gD-Crys and the dependence on temperature, protein concentration, and ionic strength. The results illustrate that at experimentally relevant conditions where stable dimers do not form, the entropic contributions are predominant in the free-energy of protein cluster formation and colloidal protein interactions, arguing against interpretations that treat B22 primarily from energetic considerations alone. Additionally, the results suggest that electrostatic interactions help to modulate the population of the different stable configurations for protein nearest-neighbor pairs, while short-range attractions determine the relative orientations of proteins within these configurations. Finally, simulation results are combined with Principal Component Analysis to identify those amino-acids/surface patches that form interprotein contacts at conditions that favor dimerization of gD-Crys. The resulting regions agree with previously found aggregation-prone sites, as well as suggesting new ones that may be important.

Dataset Information

A coarse-grained alpha-carbon protein model with anisotropic hydrogen-bonding.

Publications

A coarse-grained alpha-carbon protein model with anisotropic hydrogen-bonding.

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