Target Modeling

In drug discovery projects based on target structure, obtaining the three-dimensional (3D) structure of the target is an important starting point. As a leading provider of structural biology contract services, Creative Biostructure not only has extensive experience in experimental structure determination, but also provides comprehensive solutions for in silico target modeling and simulation.

Our Target Modeling strategies can be divided into:

1. Homology Modeling

When the primary sequence of a protein with an unknown structure is more than 30% consistent with that of a protein with a known experimental structure, the latter can be utilized as a template to predict the 3D structure of the former by computer calculation. This is the most effective method to predict protein 3D structures, which is widely applied because of its simplicity, efficiency, and relatively high accuracy. It has been shown that the protein 3D structure is more evolutionarily conserved than would be expected based on sequence conservation alone. Thus, even if the sequences are significantly different but still have detectable similarities, and the proteins will still share common structural characteristics.

Creative Biostructure can utilize one or more associated-experimental structures to construct the target model. The basic process of homology modeling (also known as template-based modeling) is as follows:

• Sequence query to obtain homologous proteins with known structures as template proteins
• Multiple sequence alignments to determine the structurally conserved regions (SCRs) and the corresponding framework of homologous proteins
• Construct the target protein 3D structure, including modeling of the main chain, side chain, and loop region, usually using methods such as copying the skeleton, constructing the side chain, complementing the missing residues and optimizing the loop region
• Energy minimization through iterative calculations
• Evaluation of structural rationality

2. Ab Initio Modeling

The template-based modeling process does not help address the basic questions on how and why a protein adopts the specific structure out of many possibilities. If there is no homology structure, or if it exists but cannot be recognized, a 3D model must be built from scratch.

The ab initio prediction strategy consists in modeling all the energy involved in the folding process of the target protein and then searching for the structure with the lowest free energy. This strategy is based on the thermodynamic hypothesis that the native structure of a protein is the one with a global minimum in free energy. Creative Biostructure has successfully built some target protein models from scratch in the past. Our experience is as follows:

• Design an accurate energy function that can distinguish between the native structure and all possible decoy structures
• Conformation search under the guidance of the designed energy function and this is an efficient search method that can quickly identify the low-energy states
• A strategy for selecting near-native models from many possible decoy pools structures

Target modeling specialists from Creative Biostructure offer customized solutions for your project and provide timely feedback during execution. Our advanced equipment and professional team ensure that high-quality models are built.