Theoretical and experimental demonstration of the importance of specific nonnative interactions in protein folding.


Abstract

Many experimental and theoretical studies have suggested a significant role for nonnative interactions in protein folding pathways, but the energetic contributions of these interactions are not well understood. We have addressed the energetics and the position specificity of nonnative hydrophobic interactions by developing a continuum coarse-grained chain model with a native-centric potential augmented by sequence-dependent hydrophobic interactions. By modeling the effect of different hydrophobicity values at various positions in the Fyn SH3 domain, we predicted energetically significant nonnative interactions that led to acceleration or deceleration of the folding rate depending on whether they were more populated in the transition state or unfolded state. These nonnative contacts were centered on position 53 in the Fyn SH3 domain, which lies in an exposed position in a 3(10)-helix. The energetic importance of the predicted nonnative interactions was confirmed experimentally by folding kinetics studies combined with double mutant thermodynamic cycles. By attaining agreement of theoretical and experimental investigations, this study provides a compelling demonstration that specific nonnative interactions can significantly influence folding energetics. Moreover, we show that a coarse-grained model with a simple consideration of hydrophobicity is sufficient for the accurate prediction of kinetically important nonnative interactions. Study holds ProTherm entries: 24648, 24649, 24650, 24651, 24652, 24653, 24654, 24655, 24656, 24657, 24658, 24659, 24660, 24661, 24662, 24663, 24664, 24665, 24666, 24667, 24668, 24669, 24670, 24671, 24672, 24673, 24674, 24675 Extra Details: 0.2 mM EDTA was added in the experiment double mutant cycles; Fyn tyrosine kinase; Go models; HP model; Langevin dynamics

Submission Details

ID: stPVeEap3

Submitter: Connie Wang

Submission Date: April 24, 2018, 8:55 p.m.

Version: 1

Publication Details
Zarrine-Afsar A;Wallin S;Neculai AM;Neudecker P;Howell PL;Davidson AR;Chan HS,Proc. Natl. Acad. Sci. U.S.A. (2008) Theoretical and experimental demonstration of the importance of specific nonnative interactions in protein folding. PMID:18626019
Additional Information

Structure view and single mutant data analysis

Study data

No weblogo for data of varying length.
Colors: D E R H K S T N Q A V I L M F Y W C G P
 

Data Distribution

Studies with similar sequences (approximate matches)

Correlation with other assays (exact sequence matches)


Relevant UniProtKB Entries

Percent Identity Matching Chains Protein Accession Entry Name
100.0 Tyrosine-protein kinase Fyn A0JNB0 FYN_BOVIN
100.0 Tyrosine-protein kinase Fyn P06241 FYN_HUMAN
100.0 Tyrosine-protein kinase Fyn P39688 FYN_MOUSE
100.0 Tyrosine-protein kinase Fyn A1Y2K1 FYN_PIG
100.0 Tyrosine-protein kinase Fyn Q62844 FYN_RAT
98.3 Tyrosine-protein kinase Fyn Q05876 FYN_CHICK
96.8 Tyrosine-protein kinase Fyn P13406 FYN_XENLA
93.2 Tyrosine-protein kinase Fyn Q6EWH2 FYNA_DANRE
91.5 Tyrosine-protein kinase Fyn F1RDG9 FYNB_DANRE
92.6 Tyrosine-protein kinase Fyn P27446 FYN_XIPHE