Protein folding from heterogeneous unfolded state revealed by time-resolved X-ray solution scattering

Kim, Tae Wu; Lee, Sang Jin; Jo, Junbeom; Kim, Jong Goo; Ki, Hosung; Kim, Chang Woo; Cho, Kwang Hyun; Choi, Jungkweon; Lee, Jae Hyuk; Wulff, Michael; Rhee, Young Min; Ihee, Hyotcherl

doi:10.1073/pnas.1913442117

Title: Protein folding from heterogeneous unfolded state revealed by time-resolved X-ray solution scattering

Journal Article · Mon Jun 15 00:00:00 EDT 2020 · Proceedings of the National Academy of Sciences of the United States of America

DOI:https://doi.org/10.1073/pnas.1913442117· OSTI ID:1642237

^[1]; Lee, Sang Jin ^[1]; Jo, Junbeom ^[1]; Kim, Jong Goo ^[1]; Ki, Hosung ^[1]; Kim, Chang Woo ^[2]; Cho, Kwang Hyun ^[2];

^[3]; Lee, Jae Hyuk ^[4]; Wulff, Michael ^[5];

^[2];

^[1]

Korea Advanced Inst. Science and Technology (KAIST), Daejeon (Korea); Inst. for Basic Science, Daejeon (Korea)
Korea Advanced Inst. Science and Technology (KAIST), Daejeon (Korea)
Inst. for Basic Science, Daejeon (Korea)
Pohang Accelerator Lab. (PAL) (Korea)
European Synchrotron Radiation Facility (ESRF), Grenoble (France)

One of the most challenging tasks in biological science is to understand how a protein folds. In theoretical studies, the hypothesis adopting a funnel-like free-energy landscape has been recognized as a prominent scheme for explaining protein folding in views of both internal energy and conformational heterogeneity of a protein. Despite numerous experimental efforts, however, comprehensively studying protein folding with respect to its global conformational changes in conjunction with the heterogeneity has been elusive. Here we investigate the redox-coupled folding dynamics of equine heart cytochrome c (cyt-c) induced by external electron injection by using time-resolved X-ray solution scattering. A systematic kinetic analysis unveils a kinetic model for its folding with a stretched exponential behavior during the transition toward the folded state. With the aid of the ensemble optimization method combined with molecular dynamics simulations, we found that during the folding the heterogeneously populated ensemble of the unfolded state is converted to a narrowly populated ensemble of folded conformations. These observations obtained from the kinetic and the structural analyses of X-ray scattering data reveal that the folding dynamics of cyt-c accompanies many parallel pathways associated with the heterogeneously populated ensemble of unfolded conformations, resulting in the stretched exponential kinetics at room temperature. This finding provides direct evidence with a view to microscopic protein conformations that the cyt-c folding initiates from a highly heterogeneous unfolded state, passes through still diverse intermediate structures, and reaches structural homogeneity by arriving at the folded state.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS); National Research Foundation of Korea (NRF); Institute for Basic Science (IBS)

Grant/Contract Number:: AC02-06CH11357; R24GM111072

OSTI ID:: 1642237

Journal Information:: Proceedings of the National Academy of Sciences of the United States of America, Vol. 117, Issue 26; ISSN 0027-8424

Publisher:: National Academy of SciencesCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 29 works

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