Distance-Guided Forward and Backward Chain-Growth Monte Carlo Method for Conformational Sampling and Structural Prediction of Antibody CDR-H3 Loops.

Ke Tang,Jie Liang,Jinfeng Zhang

doi:10.1021/acs.jctc.6b00845

Abstract

Antibodies recognize antigens through the complementary determining regions (CDR) formed by six-loop hypervariable regions crucial for the diversity of antigen specificities. Among the six CDR loops, the H3 loop is the most challenging to predict because of its much higher variation in sequence length and identity, resulting in much larger and complex structural space, compared to the other five loops. We developed a novel method based on a chain-growth sequential Monte Carlo method, called distance-guided sequential chain-growth Monte Carlo for H3 loops (DiSGro-H3). The new method samples protein chains in both forward and backward directions. It can efficiently generate low energy, near-native H3 loop structures using the conformation types predicted from the sequences of H3 loops. DiSGro-H3 performs significantly better than another ab initio method, RosettaAntibody, in both sampling and prediction, while taking less computational time. It performs comparably to template-based methods. As an ab initio method, DiSGro-H3 offers satisfactory accuracy while being able to predict any H3 loops without templates.

Highlights

Protein loops are key structural components involved in recognition and binding of small molecules or other proteins.[1,2,3] Their structures are difficult to determine experimentally due to their flexibility and irregularity
2.1 Distance-guided chain-Growth Monte Carlo for complementary determining regions (CDR) H3 Loops (DISGRO-H3) DISGRO-H3 is developed based on our previous DISGRO method.[21]
Test Sets—To assess the accuracy of DISGRO-H3 and facilitate direct comparison with the other methods, we use the test set from Ref.,[34] which we called the RA test set

Summary

Introduction

Protein loops are key structural components involved in recognition and binding of small molecules or other proteins.[1,2,3] Their structures are difficult to determine experimentally due to their flexibility and irregularity. Antibodies are a class of Y-shaped proteins produced by the immune system that identify and neutralize foreign pathogens They can recognize and bind to antigens with extraordinary affinity and specificity,[24,25] and can be used for preventing and treating various diseases, e.g. cancer,[26,27] arthritis,[28] and infectious diseases.[29] The remarkable binding specificity and affinity are determined mainly by the six hypervariable loops, referred to as the complementary determining regions (CDR). The H3 loop locates at the center of the binding site and plays important roles in determining the specificity of antibody-antigen interactions.[30,31] H3 loop is the most diverse in terms of sequence identity and length, resulting in a larger and more complex structure space. The prediction of H3 loops has not been very satisfactory due to the increased sequence length and much larger conformational space

Methods

Results

Conclusion