Predicting antibody hypervariable loop conformations. II: Minimization and molecular dynamics studies of MCPC603 from...

Area of Science:

• Structural Biology
• Computational Biochemistry
• Immunoinformatics

Background:

• Complementarity Determining Regions (CDRs) are critical for antibody-antigen binding.
• Accurate prediction of CDR loop conformations is essential for understanding antibody function and designing novel therapeutics.
• Previous methods for loop conformation prediction have limitations in accuracy and computational efficiency.

Purpose of the Study:

• To develop and apply a novel computational method for predicting protein loop conformations.
• To investigate the conformational flexibility of four specific CDRs within the MCPC603 antibody structure.
• To determine the influence of loop length and sequence-specific interactions on CDR conformation.

Main Methods:

• Generation of a large number of random backbone conformations for target loops.
• Application of energy minimization and molecular dynamics simulations to explore conformational space.
• Analysis of loop conformations considering framework interactions and sequence-specific side-chain effects.

Main Results:

• Short CDRs (H1, L2) accurately predicted using backbone-only simulations, suggesting independent folding.
• Longer CDRs (L3, H3) showed significant conformational variability, particularly at loop termini.
• Sequence-specific interactions influenced the stability of predicted conformations for longer CDRs, with only crystal-like structures being favorable for H3.

Conclusions:

• The developed method effectively predicts conformations for short CDRs, highlighting their intrinsic folding properties.
• Conformational plasticity increases with CDR loop length, influenced by framework interactions and sequence.
• Accurate prediction of longer CDR conformations requires consideration of sequence-specific side-chain interactions.