Synthetic nanomaterials from standardized protein blocks

In March, 2024, Huddy et al. in the team of David Baker (subsequently a Nobel Laureate) published a wide range of synthetic protein nanostructures self-assembled from standardized, engineered alpha-helical protein "building blocks"^[1] (). The extensively documented report, in Nature, has 32 authors^[1].

The breakthrough here is that instead of designing a single "one-off" desired nanostructure, the Baker group has first designed a series of regular building blocks that can be assembled into diverse nanostructures using straightforward geometric principles. These now enable "construction of protein nanomaterials according to ‘back of an envelope’ architectural blueprints"^[1]. There are many potential applications, such as drug delivery or catalysis, which remain to be explored.

Building Blocks

In this project, the simplest building blocks consist of anti-parallel alpha helices engineered to be straight and flat, that is twistless helix repeat (THR) protein blocks. A simple example, THR1, is 8g9j, consisting of ^[2]. Each helix is amphipathic, that is, hydrophobic on the side contacting other helixes, and hydrophilic on the side facing outwards (not shown). The 2.5 Å resolution of 8g9j enabled the modeling of all helix side chains. Non-covalent interactions between helices are nearly all apolar, with a few hydrogen bonds, and two salt bridges (not shown). The , making a highly water soluble building block. The edges of the block are "capped" with charges that prevent these blocks from binding to each other, thus enabling crystallization of this block rather than having it precipitate.

Dozens of types of building blocks were designed, synthesized, purified, and their structures and assemblies were determined^[1]. ^[3].

Assemblies

Building blocks were designed with precise angles, and with specific points of attachment between blocks. Most self-assembled into the predicted assemblies^[4], including:

Flat Assemblies

• (120_C3_A_design, branch 60°).
• (90_C4_A_design, 90°).
• (72_C5_A_design, 108°).
• (R20A_design).
• (strut_C6_21_cryo_fit).
• (strut_C6_16_design).

Cage Assemblies

• (cage_T3_5_+2_design).
• (8TL7, 4.1 Å cryo-EM).
• (cage_O4_32_design).
• (8v2d, 6.8 Å cryo-EM, the initial scene).

Inter-Chain Adhesions

In , each chain (block) adheres to three other chains. There are two "branch" adhesions (face to end) and one "handshake" adhesion (face-to-face).

Related Work

Related work from the Baker group includes Bond-centric modular design of protein assemblies by Wang et al., 2024^[5].