From Protein Design to the Energy Landscape of a Cold Unfolding Protein

Pulavarti, Surya V.S.R.K.; Maguire, Jack B.; Yuen, Shirley; Harrison, Joseph S.; Griffin, Jermel; Premkumar, Lakshmanane; Esposito, Edward A.; Makhatadze, George I.; Garcia, Angel E.; Weiss, Thomas M.; Snell, Edward H.; Kuhlman, Brian; Szyperski, Thomas

doi:10.1021/acs.jpcb.1c10750

From Protein Design to the Energy Landscape of a Cold Unfolding Protein

Journal Article · Mon Feb 07 00:00:00 EST 2022 · Journal of Physical Chemistry. B

DOI:https://doi.org/10.1021/acs.jpcb.1c10750· OSTI ID:1865037

Pulavarti, Surya V.S.R.K. ^[1]; Maguire, Jack B. ^[2]; Yuen, Shirley ^[3]; Harrison, Joseph S. ^[4]; Griffin, Jermel ^[5]; Premkumar, Lakshmanane ^[6]; Esposito, Edward A. ^[7]; ^[8]; ^[9]; Weiss, Thomas M. ^[10]; ^[11]; ^[6]; ^[1]

State Univ. of New York (SUNY), Buffalo, NY (United States)
Univ. of North Carolina, Chapel Hill, NC (United States); Menten AI Inc., Palo Alto, CA (United States)
State Univ. of New York at Buffalo, NY (United States)
Univ. of North Carolina, Chapel Hill, NC (United States); Univ. of the Pacific, Stockton, CA (United States)
State Univ. of New York at Buffalo, NY (United States); Astrix Software Technology Inc., Red Bank, NJ (United States)
Univ. of North Carolina, Chapel Hill, NC (United States)
Malvern Panalytical Inc, Northhampton, MA (United States)
Rensselaer Polytechnic Inst., Troy, NY (United States)
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Stanford Univ., CA (United States)
Hauptman-Woodward Medical Research Inst. (HWI), Buffalo, NY (United States); State Univ. of New York at Buffalo, NY (United States)

Understanding protein folding is crucial for protein sciences. The conformational spaces and energy landscapes of cold (unfolded) protein states, as well as the associated transitions, are hardly explored. Furthermore, it is not known how structure relates to the cooperativity of cold transitions, if cold and heat unfolded states are thermodynamically similar, and if cold states play important roles for protein function. We created the cold unfolding 4-helix bundle DCUB1 with a de novo designed bipartite hydrophilic/hydrophobic core featuring a hydrogen bond network which extends across the bundle in order to study the relative importance of hydrophobic versus hydrophilic protein–water interactions for cold unfolding. Structural and thermodynamic characterization resulted in the discovery of a complex energy landscape for cold transitions, while the heat unfolded state is a random coil. Below ~0 °C, the core of DCUB1 disintegrates in a largely cooperative manner, while a near-native helical content is retained. The resulting cold core-unfolded state is compact and features extensive internal dynamics. Below -5 °C, two additional cold transitions are seen, that is, (i) the formation of a water-mediated, compact, and highly dynamic dimer, and (ii) the onset of cold helix unfolding decoupled from cold core unfolding. Our results suggest that cold unfolding is initiated by the intrusion of water into the hydrophilic core network and that cooperativity can be tuned by varying the number of core hydrogen bond networks. Protein design has proven to be invaluable to explore the energy landscapes of cold states and to robustly test related theories.

View Accepted Manuscript (DOE)

Research Organization:: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)

Sponsoring Organization:: National Institutes of Health (NIH); National Science Foundation (NSF); USDOE Laboratory Directed Research and Development (LDRD) Program

Grant/Contract Number:: 89233218CNA000001; AC02-76SF00515

OSTI ID:: 1865037

Alternate ID(s):: OSTI ID: 1877194

Report Number(s):: LA-UR-21-32367

Journal Information:: Journal of Physical Chemistry. B, Journal Name: Journal of Physical Chemistry. B Journal Issue: 6 Vol. 126; ISSN 1520-6106

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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59 BASIC BIOLOGICAL SCIENCES
NMR
alkyls
cold denaturation
molecular structure
molecules
noncovalent interactions
protein design
simulation
x-rays

From Protein Design to the Energy Landscape of a Cold Unfolding Protein

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