Hydrophobic Patterns and Folding Thermodynamics-Kinetics in a 2D HP Model

Abstract

Protein folding is a process in which the linear amino acid chain is transformed into a stable three-dimensional native structure which enables the protein to carry out its function. In several neurodegenerative diseases, including Alzheimer's disease (amyloid-β) and Huntington's disease (huntingtin), a pathological mechanism is the misfolding and aggregation of specific proteins. This study quantifies the independent effect of hydrophobic proportion and spatial distribution on conformational stability and conformational search efficiency using a fully controlled 20-residue two-dimensional (2-D) HP lattice model, and a standardized simulated annealing (SA) workflow. Results showed that the total hydrophobic content was the most important factor for thermodynamic stability and the relative performance of the two distribution patterns showed a significant crossover effect. However, only at low levels of hydrophobicity (less than 40%) do contiguous hydrophobic blocks outperform dispersed ones, with evenly dispersed residues forming more symmetric globular structures, being more energy stable and compact. This pattern-dependent reversal can account for the conflicting conclusions of the previous studies that are confined to a narrow hydrophobic range. All conclusions are only applicable to the present short-chain 2D lattice system and fixed annealing parameters, and cannot be directly compared with the real physical folding time for natural proteins or transferred to longer sequence systems.