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Molecular dynamics as a tool to detect protein foldability. A mutant of domain B1 of protein G with non-native secondary structure propensities.

ABSTRACT: The usefulness of molecular dynamics to assess the structural integrity of mutants containing several mutations has been investigated. Our goal was to determine whether molecular dynamics would be able to discriminate mutants of a protein having a close-to-wild-type fold, from those that are not folded under the same conditions. We used as a model the B1 domain of protein G in which we replaced the unique central alpha-helix by the sequence of the second beta-hairpin, which has a strong intrinsic propensity to form this secondary structure in solution. In the resulting protein, one-third of the secondary structure has been replaced by a non-native one. Models of the mutants were built based on the three-dimensional structure of the wild-type GB1 domain. During 2 ns of molecular dynamics simulations on these models, mutants containing up to 10 mutations in the helix retained the native fold, while another mutant with an additional mutation unfolded. This result is in agreement with our circular dichroism and NMR experiments, which indicated that the former mutants fold into a structure similar to the wild-type, as opposed to the latter mutant which is partly unfolded. Additionally, a mutant containing six mutations scattered through the surface of the domain, and which is unfolded, was also detected by the simulation. This study suggests that molecular dynamics calculations could be performed on molecular models of mutants of a protein to evaluate their foldability, prior to a mutagenesis experiment.

SUBMITTER: Cregut D

PROVIDER: S-EPMC2144254 | biostudies-other | 1999 Feb

REPOSITORIES: biostudies-other

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Molecular dynamics as a tool to detect protein foldability. A mutant of domain B1 of protein G with non-native secondary structure propensities.

Cregut D D Serrano L L

Protein science : a publication of the Protein Society 19990201 2

The usefulness of molecular dynamics to assess the structural integrity of mutants containing several mutations has been investigated. Our goal was to determine whether molecular dynamics would be able to discriminate mutants of a protein having a close-to-wild-type fold, from those that are not folded under the same conditions. We used as a model the B1 domain of protein G in which we replaced the unique central alpha-helix by the sequence of the second beta-hairpin, which has a strong intrinsi ...[more]

PMID: 10048320

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Project description:An amino acid sequence, in the context of the solvent environment, contains all of the thermodynamic information necessary to encode a three-dimensional protein structure. To investigate the relationship between an amino acid sequence and its corresponding protein fold, a database of thermodynamic stability information was assembled that spanned 2951 residues from 44 nonhomologous proteins. This information was obtained using the COREX algorithm, which computes an ensemble-based description of the native state of a protein. It was observed that amino acid types partitioned unequally into high, medium, and low thermodynamic stability environments. Furthermore, these distributions were reproducible and were significantly different than those expected from random partitioning. To assess the structural importance of the distributions, simple fold-recognition experiments were performed based on a 3D-1D scoring matrix containing only COREX residue stability information. This procedure was able to recover amino acid sequences corresponding to correct target structures more effectively than scoring matrices derived from randomized data. High-scoring sequences were often aligned correctly with their corresponding target profiles, suggesting that calculated thermodynamic stability profiles have the potential to encode sequence information. As a control, identical fold-recognition experiments were performed on the same database of proteins using DSSP secondary structure information in the scoring matrix, instead of COREX residue stability information. The comparable performance of both approaches suggested that COREX residue stability information and secondary structure information could be of equivalent utility in more sophisticated fold-recognition techniques. The results of this work are a consequence of the idea that amino acid sequences fold not into single, rigidly stable structures but rather into thermodynamic ensembles best represented by a time-averaged structure.

Dataset Information

Molecular dynamics as a tool to detect protein foldability. A mutant of domain B1 of protein G with non-native secondary structure propensities.

Publications

Molecular dynamics as a tool to detect protein foldability. A mutant of domain B1 of protein G with non-native secondary structure propensities.

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