Tags

Type your tag names separated by a space and hit enter

Carbohydrate-binding proteins: Dissecting ligand structures through solvent environment occupancy.
J Phys Chem B 2009; 113(25):8717-24JP

Abstract

Formation of protein ligand complexes is a fundamental phenomenon in biochemistry. During the process, significant solvent reorganization is produced along the contact surface and many water molecules strongly bound to the protein's ligand binding site must be displaced. Both the thermodynamics and kinetics of this process are complex and a clear understanding at the microscopic level has been not achieved so far. Special attention has been paid to the structure of water molecules on carbohydrate recognition sites of various proteins, and many studies support the idea that displacement of these water molecules should have a crucial effect on the binding free energy. Molecular dynamics (MD) simulations in explicit water solvent is a very promising approach for this type of studies. Using MD simulations combined with statistical mechanics analysis, thermodynamic properties of these water molecules can be computed and analyzed in a comparative view. Using this idea, we developed a set of analysis tools to link solvation with ligand binding in a key carbohydrate binding protein, human galectin-1 (hGal-1). Specifically, we defined water sites (WS) in terms of the thermodynamic properties of water molecules strongly bound to protein surfaces. In the present work, we selected a group of proteins whose ligand bound complexes have been already structurally characterized in order to extend the analysis of the role of the surface associated water molecules in the ligand binding and recognition process. The selected proteins are concanavalin-A (Con-A), galectin-3 (Gal-3), cyclophilin-A (Cyp-A), and two modules CBM40 and CBM32 of the multimodular bacterial sialidase. Our results show that the probability of finding water molecules inside the WS, p(v), with respect to the bulk density is directly correlated to the likeliness of finding an hydroxyl group of the ligand in the protein-ligand complex. This information can be used to analyze in detail the solvation structure of the carbohydrate recognition domain (CRD) and its relation to the possible protein ligand complexes and suggests addition of OH-containing functional groups to displace water from high p(v) WS to enhance drugs, specially glycomimetic-drugs, protein affinity, and/or specificity.

Authors+Show Affiliations

Departamento de Quimica Inorganica, Analitica, y Quimica Fisica, INQUIMAE-CONICET, Universidad de Buenos Aires, Argentina.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

19485380

Citation

Gauto, Diego F., et al. "Carbohydrate-binding Proteins: Dissecting Ligand Structures Through Solvent Environment Occupancy." The Journal of Physical Chemistry. B, vol. 113, no. 25, 2009, pp. 8717-24.
Gauto DF, Di Lella S, Guardia CM, et al. Carbohydrate-binding proteins: Dissecting ligand structures through solvent environment occupancy. J Phys Chem B. 2009;113(25):8717-24.
Gauto, D. F., Di Lella, S., Guardia, C. M., Estrin, D. A., & Martí, M. A. (2009). Carbohydrate-binding proteins: Dissecting ligand structures through solvent environment occupancy. The Journal of Physical Chemistry. B, 113(25), pp. 8717-24. doi:10.1021/jp901196n.
Gauto DF, et al. Carbohydrate-binding Proteins: Dissecting Ligand Structures Through Solvent Environment Occupancy. J Phys Chem B. 2009 Jun 25;113(25):8717-24. PubMed PMID: 19485380.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carbohydrate-binding proteins: Dissecting ligand structures through solvent environment occupancy. AU - Gauto,Diego F, AU - Di Lella,Santiago, AU - Guardia,Carlos M A, AU - Estrin,Darío A, AU - Martí,Marcelo A, PY - 2009/6/3/entrez PY - 2009/6/3/pubmed PY - 2009/8/18/medline SP - 8717 EP - 24 JF - The journal of physical chemistry. B JO - J Phys Chem B VL - 113 IS - 25 N2 - Formation of protein ligand complexes is a fundamental phenomenon in biochemistry. During the process, significant solvent reorganization is produced along the contact surface and many water molecules strongly bound to the protein's ligand binding site must be displaced. Both the thermodynamics and kinetics of this process are complex and a clear understanding at the microscopic level has been not achieved so far. Special attention has been paid to the structure of water molecules on carbohydrate recognition sites of various proteins, and many studies support the idea that displacement of these water molecules should have a crucial effect on the binding free energy. Molecular dynamics (MD) simulations in explicit water solvent is a very promising approach for this type of studies. Using MD simulations combined with statistical mechanics analysis, thermodynamic properties of these water molecules can be computed and analyzed in a comparative view. Using this idea, we developed a set of analysis tools to link solvation with ligand binding in a key carbohydrate binding protein, human galectin-1 (hGal-1). Specifically, we defined water sites (WS) in terms of the thermodynamic properties of water molecules strongly bound to protein surfaces. In the present work, we selected a group of proteins whose ligand bound complexes have been already structurally characterized in order to extend the analysis of the role of the surface associated water molecules in the ligand binding and recognition process. The selected proteins are concanavalin-A (Con-A), galectin-3 (Gal-3), cyclophilin-A (Cyp-A), and two modules CBM40 and CBM32 of the multimodular bacterial sialidase. Our results show that the probability of finding water molecules inside the WS, p(v), with respect to the bulk density is directly correlated to the likeliness of finding an hydroxyl group of the ligand in the protein-ligand complex. This information can be used to analyze in detail the solvation structure of the carbohydrate recognition domain (CRD) and its relation to the possible protein ligand complexes and suggests addition of OH-containing functional groups to displace water from high p(v) WS to enhance drugs, specially glycomimetic-drugs, protein affinity, and/or specificity. SN - 1520-6106 UR - https://www.unboundmedicine.com/medline/citation/19485380/Carbohydrate_binding_proteins:_Dissecting_ligand_structures_through_solvent_environment_occupancy_ L2 - https://dx.doi.org/10.1021/jp901196n DB - PRIME DP - Unbound Medicine ER -