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How does a simplified-sequence protein fold?

ABSTRACT: To investigate a putatively primordial protein we have simplified the sequence of a 56-residue alpha/beta fold (the immunoglobulin-binding domain of protein G) by replacing it with polyalanine, polythreonine, and diglycine segments at regions of the sequence that in the folded structure are alpha-helical, beta-strand, and turns, respectively. Remarkably, multiple folding and unfolding events are observed in a 15-micros molecular dynamics simulation at 330 K. The most stable state (populated at approximately 20%) of the simplified-sequence variant of protein G has the same alpha/beta topology as the wild-type but shows the characteristics of a molten globule, i.e., loose contacts among side chains and lack of a specific hydrophobic core. The unfolded state is heterogeneous and includes a variety of alpha/beta topologies but also fully alpha-helical and fully beta-sheet structures. Transitions within the denatured state are very fast, and the molten-globule state is reached in <1 micros by a framework mechanism of folding with multiple pathways. The native structure of the wild-type is more rigid than the molten-globule conformation of the simplified-sequence variant. The difference in structural stability and the very fast folding of the simplified protein suggest that evolution has enriched the primordial alphabet of amino acids mainly to optimize protein function by stabilization of a unique structure with specific tertiary interactions.

SUBMITTER: Guarnera E

PROVIDER: S-EPMC2749778 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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How does a simplified-sequence protein fold?

Guarnera Enrico E Pellarin Riccardo R Caflisch Amedeo A

Biophysical journal 20090901 6

To investigate a putatively primordial protein we have simplified the sequence of a 56-residue alpha/beta fold (the immunoglobulin-binding domain of protein G) by replacing it with polyalanine, polythreonine, and diglycine segments at regions of the sequence that in the folded structure are alpha-helical, beta-strand, and turns, respectively. Remarkably, multiple folding and unfolding events are observed in a 15-micros molecular dynamics simulation at 330 K. The most stable state (populated at a ...[more]

PMID: 19751679

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Project description:BackgroundSequence matching is extremely important for applications throughout biology, particularly for discovering information such as functional and evolutionary relationships, and also for discriminating between unimportant and disease mutants. At present the functions of a large fraction of genes are unknown; improvements in sequence matching will improve gene annotations. Universal amino acid substitution matrices such as Blosum62 are used to measure sequence similarities and to identify distant homologues, regardless of the structure class. However, such single matrices do not take into account important structural information evident within the different topologies of proteins and treats substitutions within all protein folds identically. Others have suggested that the use of structural information can lead to significant improvements in sequence matching but this has not yet been very effective. Here we develop novel substitution matrices that include not only general sequence information but also have a topology specific component that is unique for each CATH topology. This novel feature of using a combination of sequence and structure information for each protein topology significantly improves the sequence matching scores for the sequence pairs tested. We have used a novel multi-structure alignment method for each homology level of CATH in order to extract topological information.ResultsWe obtain statistically significant improved sequence matching scores for 73 % of the alpha helical test cases. On average, 61 % of the test cases showed improvements in homology detection when structure information was incorporated into the substitution matrices. On average z-scores for homology detection are improved by more than 54 % for all cases, and some individual cases have z-scores more than twice those obtained using generic matrices. Our topology specific similarity matrices also outperform other traditional similarity matrices and single matrix based structure methods. When default amino acid substitution matrix in the Psi-blast algorithm is replaced by our structure-based matrices, the structure matching is significantly improved over conventional Psi-blast. It also outperforms results obtained for the corresponding HMM profiles generated for each topology.ConclusionsWe show that by incorporating topology-specific structure information in addition to sequence information into specific amino acid substitution matrices, the sequence matching scores and homology detection are significantly improved. Our topology specific similarity matrices outperform other traditional similarity matrices, single matrix based structure methods, also show improvement over conventional Psi-blast and HMM profile based methods in sequence matching. The results support the discriminatory ability of the new amino acid similarity matrices to distinguish between distant homologs and structurally dissimilar pairs.

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How does a simplified-sequence protein fold?

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How does a simplified-sequence protein fold?

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