Unifying Polar and Hydrophobic Models of Ice Recognition by Antifreeze Glycoproteins
Year: 2026
Type: article
Abstract: Antifreeze glycoproteins (AFGPs) enable polar organisms to survive at subzero temperatures by inhibiting ice growth through selective association with specific crystallographic planes. However, the molecular basis of this interaction and its remarkable selectivity remain incompletely understood, and both polar and hydrophobic binding models have been proposed. Here, we combine the synthesis of AFGP variants with high-resolution NMR spectroscopy, antifreeze activity measurements, and molecular dynamics simulations to investigate the molecular determinants of ice recognition. Minimally perturbative chemical modifications, including site-specific deuteration and fluorination, were used to probe the contributions of nonpolar and polar interactions while preserving the characteristic AFGP conformation. The combined structure–activity relationships and computational analyses support an integrative binding model that provides a unified and parsimonious interpretation of the experimental observations. Within this framework, our experimental evidence is consistent with the view that dispersive interactions involving peptide and carbohydrate methyl groups favor productive association with the ice surface, whereas carbohydrate hydroxyl groups, together with sugar- and backbone-associated water molecules, contribute polar interactions that promote selective and persistent binding. This model reconciles key aspects of previously proposed polar and hydrophobic descriptions and provides a molecular rationale for the characteristic plane selectivity of AFGPs and the conservation of specific sequence motifs. More broadly, our results highlight minimally perturbative isotopic substitution and fluorinated molecular editing as useful chemical strategies for probing weak dispersive contributions to complex molecular recognition processes while preserving native molecular architecture.
DOI: 10.1021/jacs.6c14020
Authors: Alejandro Villacampa, Julio Zabalza, Alba Nin-Hill, Akari Yamauchi, Alicia Asín, Andrés G. Santana, Mattia Ghirardello, Ismael Compañón, Tatsuya Arai, Qinghua Liao, Laura Díaz-Casado, Claudia Sanchez-García, Hiroshi Hinou, Pierre Çarçabal, Emilio J. Cocinero, Fayna García Martín, Alberto Avenoza, Jesús H. Busto, Ramón Hurtado-Guerrero, Jesús M. Peregrina, Ana M. Gómez, Shin-Ichiro Nishimura, Jesús Jiménez-Barbero, Carme Rovira, Benjamin G. Davis, Ester Jiménez-Moreno, Sakae Tsuda, Francisco Corzana, Juan L. Asensio
Institutions: Instituto de Química Orgánica General, Universidad de La Rioja, Universitat de Barcelona, Hokkaido University, Consejo Superior de Investigaciones Científicas, Instituto de Productos Naturales y Agrobiología, Université Paris-Sud, Centre National de la Recherche Scientifique, University of the Basque Country, Instituto Biofisika, University of Copenhagen, Universidad de Zaragoza, Fundacion Agencia Aragonesa para la Investigacion y el Desarrollo, Ikerbasque, Centro de Investigación Biomédica en Red de Enfermedades Respiratorias, Institució Catalana de Recerca i Estudis Avançats, University of Oxford, Rosalind Franklin Institute
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W7225826626