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Except this exact thing was accomplished and published a few months ago [1, 2]. The Baker lab at the University of Washington designed a synthetic fluorescent

Except this exact thing was accomplished and published a few months ago [1, 2]. The Baker lab at the University of Washington designed a synthetic fluorescent protein, de novo. [1] Meta-Meta-Article: https://www.bakerlab.org/index.php/2019/01/02/nature-article-ipd-work-voted-2018-readers-choice/ https://www.bakerlab.org/index.php/2019/01/02/nature-article... [2] Actual paper: https://www.nature.com/articles/s41586-018-0509-0 https://www.nature.com/articles/s41586-018-0509-0

iso1337 8y ago
eh, it still took ~56 real-world attempts to get two functional designs. That's not even quantifying how strongly they fluoresce, and other qualitative/quantitative aspects (eg, how good of a GFP were these proteins). It's very impressive, and the Baker lab has done amazing stuff, but we are a long ways off from rational design. From the paper: "Synthetic genes encoding the 56 designs were obtained and the proteins were expressed in E. coli. Thirty-eight of the proteins were wellexpressed and soluble; SEC and far-ultraviolet CD spectroscopy showed that 20 were monomeric β-sheet proteins (Supplementary Table 3). Four of the oligomer-forming designs became monomeric upon incorporation of a disulfide bond between the N-terminal 3–10 helix and the barrel β-strands. The crystal structure of one of the monomeric designs (b10) was solved to 2.1 Å, and was found to be very close to the design model (0.57 Å backbone r.m.s.d., Fig. 3c)." "Two of the 20 monomeric designs—b11 and b32—were found to activate DFHBI fluorescence by 12- and 8-fold with binding dissociation constants (KD) values of 12.8 and 49.8 μM, respectively (Extended Data Fig. 6f)"
etrautmann 8y ago
Incredibly cool! Even if this took lots of iteration, to me this represents an important step (if my understanding of the details is correct). As a side note, this is why I appreciate HN, never would have seen this paper otherwise.
vstuart 8y ago
Nice! More recently (Jan 2019) from the same group: De novo Design of Potent and Selective Mimics of IL-2 and IL-15: https://www.nature.com/articles/s41586-018-0830-7 https://www.nature.com/articles/s41586-018-0830-7 Lab's accompanying media post: https://www.bakerlab.org/index.php/2019/01/09/potent-anti-cancer-proteins-fewer-side-effects/ https://www.bakerlab.org/index.php/2019/01/09/potent-anti-ca... " Potent anti-cancer proteins with fewer side effects. Today we report in Nature the first de novo designed proteins with anti-cancer activity. These compact molecules were designed to stimulate the same receptors as IL-2, a powerful immunotherapeutic drug, while avoiding unwanted off-target receptor interactions. ..." A remarkable and powerful achievement.

iso1337 8y ago

eh, it still took ~56 real-world attempts to get two functional designs. That's not even quantifying how strongly they fluoresce, and other qualitative/quantitative aspects (eg, how good of a GFP were these proteins). It's very impressive, and the Baker lab has done amazing stuff, but we are a long ways off from rational design. From the paper: "Synthetic genes encoding the 56 designs were obtained and the proteins were expressed in E. coli. Thirty-eight of the proteins were wellexpressed and soluble; SEC and far-ultraviolet CD spectroscopy showed that 20 were monomeric β-sheet proteins (Supplementary Table 3). Four of the oligomer-forming designs became monomeric upon incorporation of a disulfide bond between the N-terminal 3–10 helix and the barrel β-strands. The crystal structure of one of the monomeric designs (b10) was solved to 2.1 Å, and was found to be very close to the design model (0.57 Å backbone r.m.s.d., Fig. 3c)." "Two of the 20 monomeric designs—b11 and b32—were found to activate DFHBI fluorescence by 12- and 8-fold with binding dissociation constants (KD) values of 12.8 and 49.8 μM, respectively (Extended Data Fig. 6f)"

etrautmann 8y ago

Incredibly cool! Even if this took lots of iteration, to me this represents an important step (if my understanding of the details is correct). As a side note, this is why I appreciate HN, never would have seen this paper otherwise.

vstuart 8y ago

Nice! More recently (Jan 2019) from the same group: De novo Design of Potent and Selective Mimics of IL-2 and IL-15: https://www.nature.com/articles/s41586-018-0830-7 https://www.nature.com/articles/s41586-018-0830-7 Lab's accompanying media post: https://www.bakerlab.org/index.php/2019/01/09/potent-anti-cancer-proteins-fewer-side-effects/ https://www.bakerlab.org/index.php/2019/01/09/potent-anti-ca... " Potent anti-cancer proteins with fewer side effects. Today we report in Nature the first de novo designed proteins with anti-cancer activity. These compact molecules were designed to stimulate the same receptors as IL-2, a powerful immunotherapeutic drug, while avoiding unwanted off-target receptor interactions. ..." A remarkable and powerful achievement.