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Quantifying the Sources of Kinetic Frustration in Folding Simulations of Small Proteins.

ABSTRACT: Experiments and atomistic simulations of polypeptides have revealed structural intermediates that promote or inhibit conformational transitions to the native state during folding. We invoke a concept of "kinetic frustration" to quantify the prevalence and impact of these behaviors on folding rates within a large set of atomistic simulation data for 10 fast-folding proteins, where each protein's conformational space is represented as a Markov state model of conformational transitions. Our graph theoretic approach addresses what conformational features correlate with folding inhibition and therefore permits comparison among features within a single protein network and also more generally between proteins. Nonnative contacts and nonnative secondary structure formation can thus be quantitatively implicated in inhibiting folding for several of the tested peptides.

SUBMITTER: Savol AJ

PROVIDER: S-EPMC4132847 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Quantifying the Sources of Kinetic Frustration in Folding Simulations of Small Proteins.

Savol Andrej J AJ Chennubhotla Chakra S CS

Journal of chemical theory and computation 20140613 8

Experiments and atomistic simulations of polypeptides have revealed structural intermediates that promote or inhibit conformational transitions to the native state during folding. We invoke a concept of "kinetic frustration" to quantify the prevalence and impact of these behaviors on folding rates within a large set of atomistic simulation data for 10 fast-folding proteins, where each protein's conformational space is represented as a Markov state model of conformational transitions. Our graph t ...[more]

PMID: 25136267

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Project description:The thermodynamic hypothesis of Anfinsen postulates that structures and stabilities of globular proteins are determined by their amino acid sequences. Chain topology, however, is known to influence the folding reaction, in that motifs with a preponderance of local interactions typically fold more rapidly than those with a larger fraction of nonlocal interactions. Together, the topology and sequence can modulate the energy landscape and influence the rate at which the protein folds to the native conformation. To explore the relationship of sequence and topology in the folding of beta alpha-repeat proteins, which are dominated by local interactions, we performed a combined experimental and simulation analysis on two members of the flavodoxin-like, alpha/beta/alpha sandwich fold. Spo0F and the N-terminal receiver domain of NtrC (NT-NtrC) have similar topologies but low sequence identity, enabling a test of the effects of sequence on folding. Experimental results demonstrated that both response-regulator proteins fold via parallel channels through highly structured submillisecond intermediates before accessing their cis prolyl peptide bond-containing native conformations. Global analysis of the experimental results preferentially places these intermediates off the productive folding pathway. Sequence-sensitive G?-model simulations conclude that frustration in the folding in Spo0F, corresponding to the appearance of the off-pathway intermediate, reflects competition for intra-subdomain van der Waals contacts between its N- and C-terminal subdomains. The extent of transient, premature structure appears to correlate with the number of isoleucine, leucine, and valine (ILV) side chains that form a large sequence-local cluster involving the central beta-sheet and helices alpha2, alpha 3, and alpha 4. The failure to detect the off-pathway species in the simulations of NT-NtrC may reflect the reduced number of ILV side chains in its corresponding hydrophobic cluster. The location of the hydrophobic clusters in the structure may also be related to the differing functional properties of these response regulators. Comparison with the results of previous experimental and simulation analyses on the homologous CheY argues that prematurely folded unproductive intermediates are a common property of the beta alpha-repeat motif.

Dataset Information

Quantifying the Sources of Kinetic Frustration in Folding Simulations of Small Proteins.

Publications

Quantifying the Sources of Kinetic Frustration in Folding Simulations of Small Proteins.

Similar Datasets

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