From Proteopedia

Revision as of 11:07, 10 April 2025

Structure

Introduction

What are Minibinders?

These mini proteins target the interaction between ACE2 and COVID-19 spike protein ^[1]. The mini binders are small proteins carefully designed to bind to the COVID-19 spike protein with a greater affinity than ACE2 ^[1]. These mini binders were able to reduce the viral burden of SARS-CoV-2 in mice ^[2]. These proteins were de novo (from scratch) designs to mimic the ACE2 helix, but have a lower dissociation constant, yielding a greater affinity for the spike protein ^[1]. can give a better explanation as to how these proteins were designed.

COVID-19 Disease Pathway

Understanding the pathway of the COVID-19 virus is essential to understanding the mechanism in which the virus’ surface proteins attach to the mini binders. The COVID-19 virus has spike proteins on its surface that bind to the host cell receptor known as ACE2 ^[3]. The activated spike protein is able to cleave itself into S1 and S2 subunits ^[4]. The S2 subunit is in charge of viral entry and does this through conformational changes ^[4]. The S2 subunit will insert it's FP domain into the host cell's membrane, and this will trigger an interaction with the HR2 domain and HR1 trimer to form the 6-helical bundle to bring the viral envelope and cell membrane in close enough distance for viral fusion and ultimately viral entry ^[4]. Once the virus is within the host cell, it is able to translate viral proteins, eliciting an immune response and spreading the viral particles throughout the body ^[4].

COVID-19 Viral Infection Interruption

The primary goal of the mini binders is to prevent the spike proteins from binding to ACE2, and when the mini binders are bound to the spike protein, the virus is unable to anchor itself to the host protein ^[1]. Because the mini binders have a greater binding affinity than ACE2 for the spike protein, they are able to effectively prevent the entry of the virus and ultimately prevent an immune response ^[1]. Targeting this specific interaction between the COVID-19 spike protein has proven effective and is hopeful target for future therapeutics to treat the virus ^[4].

Design

These mini binders, LCB1 and AHB2, were designed from “scratch” (de novo) with the intention to mimic the binding of ACE2 to spike protein (insert citation). Using Rotamer Interaction Field (RIF) docking, the proteins were able to make the most efficient bonding using the ACE2 spike protein binding interface (insert citation). Using Site Saturation Mutagenesis (SSM), every residue in the minibinder’s helix scaffold will be substituted with each of the 20 amino acids, one at a time (insert citation). Forming SSM libraries, each of the libraries converged on a small number of closely related sequences, and from these libraries, the design was selected for LCB1 and AHB2 to find the sequence that yields a protein with a high affinity for the spike proteins receptor binding domain (insert).

spinqualitylabelsall models Caption for this structure Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image This is a default text for your page '. Click above on edit this page' to modify. Be careful with the < and > signs. You may include any references to papers as in: the use of JSmol in Proteopedia [5] or to the article describing Jmol [6] to the rescue. This is an image of LCB1 bound to the RBD of a spike protein. [1]. Figure 1. The coolest image ever! This is the link to the salt bridge Contents 1 Function 2 Disease 3 Relevance 4 Structural highlights Function Disease Relevance Structural highlights This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.