TY - JOUR
T1 - Knowledge-based potential for positioning membrane-associated structures and assessing residue-specific energetic contributions
AU - Schramm, Chaim A.
AU - Hannigan, Brett T.
AU - Donald, Jason E.
AU - Keasar, Chen
AU - Saven, Jeffrey G.
AU - Degrado, William F.
AU - Samish, Ilan
N1 - Funding Information:
We thank Cinque S. Soto, Nathan H. Joh, Alessandro Senes, and Andrei L. Lomize for fruitful discussions. We thank Christopher M. MacDermaid for assistance regarding Figure 1 . We thank financial support from NIH (GM54616 to W.F.D. and HL085303 to J.G.S.), DOD (NDSEG fellowship to B.T.H.), the Human Frontiers Science Program (to I.S.), and NSF (DMR 0520020 to J.G.S. and MRSEC and URSCC to W.F.D.). W.F.D., J.G.S., C.A.S., and I.S. designed research; I.S. and C.A.S. performed research; B.T.H. and I.S. fit the data; J.E.D. performed the original E z -Profile study; C.K. contributed the MESHI and adapted it with I.S. for this study; all authors analyzed the data; C.A.S. and I.S. wrote the paper with contributions from the other authors.
PY - 2012/5/9
Y1 - 2012/5/9
N2 - The complex hydrophobic and hydrophilic milieus of membrane-associated proteins pose experimental and theoretical challenges to their understanding. Here, we produce a nonredundant database to compute knowledge-based asymmetric cross-membrane potentials from the per-residue distributions of C β, Cγ and functional group atoms. We predict transmembrane and peripherally associated regions from genomic sequence and position peptides and protein structures relative to the bilayer (available at http://www.degradolab.org/ez). The pseudo-energy topological landscapes underscore positional stability and functional mechanisms demonstrated here for antimicrobial peptides, transmembrane proteins, and viral fusion proteins. Moreover, experimental effects of point mutations on the relative ratio changes of dual-topology proteins are quantitatively reproduced. The functional group potential and the membrane-exposed residues display the largest energetic changes enabling to detect native-like structures from decoys. Hence, focusing on the uniqueness of membrane-associated proteins and peptides, we quantitatively parameterize their cross-membrane propensity, thus facilitating structural refinement, characterization, prediction, and design.
AB - The complex hydrophobic and hydrophilic milieus of membrane-associated proteins pose experimental and theoretical challenges to their understanding. Here, we produce a nonredundant database to compute knowledge-based asymmetric cross-membrane potentials from the per-residue distributions of C β, Cγ and functional group atoms. We predict transmembrane and peripherally associated regions from genomic sequence and position peptides and protein structures relative to the bilayer (available at http://www.degradolab.org/ez). The pseudo-energy topological landscapes underscore positional stability and functional mechanisms demonstrated here for antimicrobial peptides, transmembrane proteins, and viral fusion proteins. Moreover, experimental effects of point mutations on the relative ratio changes of dual-topology proteins are quantitatively reproduced. The functional group potential and the membrane-exposed residues display the largest energetic changes enabling to detect native-like structures from decoys. Hence, focusing on the uniqueness of membrane-associated proteins and peptides, we quantitatively parameterize their cross-membrane propensity, thus facilitating structural refinement, characterization, prediction, and design.
UR - http://www.scopus.com/inward/record.url?scp=84861038844&partnerID=8YFLogxK
U2 - 10.1016/j.str.2012.03.016
DO - 10.1016/j.str.2012.03.016
M3 - Article
AN - SCOPUS:84861038844
SN - 0969-2126
VL - 20
SP - 924
EP - 935
JO - Structure
JF - Structure
IS - 5
ER -