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De Novo Self-Assembling Collagen Heterotrimers Using Explicit Positive and Negative Design

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Fei Xu‡, Lei Zhang§, Ronald L. Koder§ and Vikas Nanda*‡

^‡ Department of Biochemistry, Robert Wood Johnson Medical School, UMDNJ, and Center for Advanced Biotechnology and Medicine, Piscataway, New Jersey 08854

^§ Department of Physics, The City College of New York, New York, New York 10031

Biochemistry, 2010, 49 (11), pp 2307–2316

DOI: 10.1021/bi902077d

Publication Date (Web): February 19, 2010

*To whom correspondence should be addressed. E-mail: nanda@cabm.rutgers.edu.

† Funding Statement

V.N. acknowledges support from the NIH Director’s New Innovator Award Program, 1-DP2-OD006478-01. V.N. and F.X. acknowledge support from the NSF BMAT Program, DMR-0907273. R.L.K. acknowledges supported by the following grants: MCB-0920448 from the NSF, MCB-5G12 RR03060 toward support for the NMR facilities at the City College of New York, P41 GM-66354 to the New York Structural Biology Center, and infrastructure support from NIH 5G12 RR03060 from the National Center for Research Resources.

Section:

General Biochemistry

Abstract

We sought to computationally design model collagen peptides that specifically associate as heterotrimers. Computational design has been successfully applied to the creation of new protein folds and functions. Despite the high abundance of collagen and its key role in numerous biological processes, fibrous proteins have received little attention as computational design targets. Collagens are composed of three polypeptide chains that wind into triple helices. We developed a discrete computational model to design heterotrimer-forming collagen-like peptides. Stability and specificity of oligomerization were concurrently targeted using a combined positive and negative design approach. The sequences of three 30-residue peptides, A, B, and C, were optimized to favor charge-pair interactions in an ABC heterotrimer, while disfavoring the 26 competing oligomers (i.e., AAA, ABB, BCA). Peptides were synthesized and characterized for thermal stability and triple-helical structure by circular dichroism and NMR. A unique A:B:C-type species was not achieved. Negative design was partially successful, with only A + B and B + C competing mixtures formed. Analysis of computed versus experimental stabilities helps to clarify the role of electrostatics and secondary-structure propensities determining collagen stability and to provide important insight into how subsequent designs can be improved.

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This article has been cited by 2 ACS Journal articles (2 most recent appear below).

Computational Design of a Collagen A:B:C-Type Heterotrimer
Fei Xu, Sohail Zahid, Teresita Silva, and Vikas Nanda
Journal of the American Chemical Society2011 133 (39), 15260-15263
- Computational Design of a Collagen A:B:C-Type Heterotrimer
  Fei Xu, Sohail Zahid, Teresita Silva, and Vikas Nanda
  Journal of the American Chemical Society2011 133 (39), 15260-15263
  We have successfully designed an A:B:C collagen peptide heterotrimer using an automated computational approach. The algorithm maximizes the energy gap between the target and competing misfolded states while enforcing a minimum target stability. Circular ...
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links
Positive and Negative Design Leads to Compositional Control in AAB Collagen Heterotrimers
Lesley E. R. O’Leary, Jorge A. Fallas, and Jeffrey D. Hartgerink
Journal of the American Chemical Society2011 133 (14), 5432-5443
- Positive and Negative Design Leads to Compositional Control in AAB Collagen Heterotrimers
  Lesley E. R. O’Leary, Jorge A. Fallas, and Jeffrey D. Hartgerink
  Journal of the American Chemical Society2011 133 (14), 5432-5443
  Although collagen is the most abundant protein in the human body and has at least 28 types, research involving collagen mimetic systems only recently began to consider the innate ability of collagen to control helix composition and register. Collagen ...
  Abstract | Full Text HTML | Hi-Res PDF | PDF w/ Links