Abstract
In this review we discuss the role of protonation states in receptor-ligand interactions, providing experimental evidences and computational predictions that complex formation may involve titratable groups with unusual pKa’s and that protonation states frequently change from unbound to bound states. These protonation changes result in proton uptake/release, which in turn causes the pHdependence of the binding. Indeed, experimental data strongly suggest that almost any binding is pH-dependent and to be correctly modeled, the protonation states must be properly assigned prior to and after the binding. One may accurately predict the protonation states when provided with the structures of the unbound proteins and their complex; however, the modeling becomes much more complicated if the bound state has to be predicted in a docking protocol or if the structures of either bound or unbound receptor-ligand are not available. The major challenges that arise in these situations are the coupling between binding and protonation states, and the conformational changes induced by the binding and ionization states of titratable groups. In addition, any assessment of the protonation state, either before or after binding, must refer to the pH of binding, which is frequently unknown. Thus, even if the pKa’s of ionizable groups can be correctly assigned for both unbound and bound state, without knowing the experimental pH one cannot assign the corresponding protonation states, and consequently one cannot calculate the resulting proton uptake/release. It is pointed out, that while experimental pH may not be the physiological pH and binding may involve proton uptake/release, there is a tendency that the native receptor-ligand complexes have evolved toward specific either subcellular or tissue characteristic pH at which the proton uptake/release is either minimal or absent.
Keywords: Protonation states, receptor-ligand interactions, pKa calculations, pH-dependence, electrostatics.
Current Pharmaceutical Design
Title:The Role of Protonation States in Ligand-Receptor Recognition and Binding
Volume: 19 Issue: 23
Author(s): Marharyta Petukh, Shannon Stefl and Emil Alexov
Affiliation:
Keywords: Protonation states, receptor-ligand interactions, pKa calculations, pH-dependence, electrostatics.
Abstract: In this review we discuss the role of protonation states in receptor-ligand interactions, providing experimental evidences and computational predictions that complex formation may involve titratable groups with unusual pKa’s and that protonation states frequently change from unbound to bound states. These protonation changes result in proton uptake/release, which in turn causes the pHdependence of the binding. Indeed, experimental data strongly suggest that almost any binding is pH-dependent and to be correctly modeled, the protonation states must be properly assigned prior to and after the binding. One may accurately predict the protonation states when provided with the structures of the unbound proteins and their complex; however, the modeling becomes much more complicated if the bound state has to be predicted in a docking protocol or if the structures of either bound or unbound receptor-ligand are not available. The major challenges that arise in these situations are the coupling between binding and protonation states, and the conformational changes induced by the binding and ionization states of titratable groups. In addition, any assessment of the protonation state, either before or after binding, must refer to the pH of binding, which is frequently unknown. Thus, even if the pKa’s of ionizable groups can be correctly assigned for both unbound and bound state, without knowing the experimental pH one cannot assign the corresponding protonation states, and consequently one cannot calculate the resulting proton uptake/release. It is pointed out, that while experimental pH may not be the physiological pH and binding may involve proton uptake/release, there is a tendency that the native receptor-ligand complexes have evolved toward specific either subcellular or tissue characteristic pH at which the proton uptake/release is either minimal or absent.
Export Options
About this article
Cite this article as:
Petukh Marharyta, Stefl Shannon and Alexov Emil, The Role of Protonation States in Ligand-Receptor Recognition and Binding, Current Pharmaceutical Design 2013; 19 (23) . https://dx.doi.org/10.2174/1381612811319230004
DOI https://dx.doi.org/10.2174/1381612811319230004 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Subcutaneous Immunoglobulins: A Promising Alternative for Immunomodulation?
Current Pharmaceutical Design Designing of Novel Carbonic Anhydrase Inhibitors and Activators
Current Medicinal Chemistry - Cardiovascular & Hematological Agents Distinct Functions of Retinoic Acid Receptor Beta Isoforms: Implications for Targeted Therapy
Endocrine, Metabolic & Immune Disorders - Drug Targets Bradykinin Receptors in Ischemic Injury
Current Neurovascular Research Inspiratory and Expiratory Chest High-resolution CT: Small-airway Disease Evaluation in Patients with COVID-19
Current Medical Imaging Liposome-Encapsulated Photosensitizers Against Bacteria
Recent Patents on Anti-Infective Drug Discovery Telomeric G-Quadruplex Architecture and Interactions with Potential Drugs
Current Pharmaceutical Design Evaluation of Cell-free Expression System for the Production of Soluble and Functional Human GPCR N-formyl Peptide Receptors
Protein & Peptide Letters Acetylcholinesterase Inhibitors and Drugs Acting on Muscarinic Receptors- Potential Crosstalk of Cholinergic Mechanisms During Pharmacological Treatment
Current Neuropharmacology Lecithin (Phosphatidylcholine): Healthy Dietary Supplement or Dangerous Toxin?
The Natural Products Journal Clinical Use of Rituximab in Patients with HIV Related Lymphoma and Multicentric Castlemans Disease
Current Drug Delivery miR-21 and let-7 in the Ras and NF-κB Pathways
MicroRNA Gastrin-Releasing Peptide as a Molecular Target for Inflammatory Diseases: An Update
Inflammation & Allergy - Drug Targets (Discontinued) Advancement in Microsponge Drug Delivery System: Preparation Methods, Patents and Commercial Utility
Recent Patents on Drug Delivery & Formulation Human Neural Stem and Progenitor Cells: In Vitro and In Vivo Properties, and Potential for Gene Therapy and Cell Replacement in the CNS
Current Gene Therapy High-Density Lipoprotein Quantity or Quality for Cardiovascular Prevention?
Current Pharmaceutical Design Gemini Surfactant Based Carriers in Gene and Drug Delivery
Current Medicinal Chemistry Patent Selections:
Recent Patents on Anti-Infective Drug Discovery Biomarkers of Osteoarthritis: A Review of Recent Research Progress on Soluble Biochemical Markers, Published Patents and Areas for Future Development
Recent Patents on Biomarkers Nanostructures for Drug Delivery to the Brain
Current Medicinal Chemistry