WHAT IS MOLECULAR SENSING
Current concept of interaction between biological molecules
Understanding how biomolecules recognize each other is very important to protein engineering and ligand (drug) design aspects of the drug and vaccine development. According to the current widely accepted concept, the first contact between interacting molecules is achieved accidentally by the thermal motions that cause molecular wander. Success of this interaction mainly depends on the steric complementarity between interacting biomolecules, which is based on two fundamental hypotheses: ‘lock-and-key’ hypothesis (proposed by Fischer 1894) and ‘induced fit’ hypothesis. Electrostatic complementarity further restricts the binding of inappropriate molecules since the ligand must contain correctly placed complementary charged atoms for interaction to occur.
The protein–protein association generally occurs at rates that are 103 – 104 times faster than what would be expected from simple considerations of collision frequencies and steric/electrostatic complementarity, which assume that productive binding occurs only when the molecules collide within 2Å of their final binding site (Northrup and Erickson, Proc Natl Acad Sci USA 1992;89:3338).
In order to overcome the discrepancy between theoretically estimated values and real values scientists have suggested that the resonant interaction between biological molecules based on the appearance of frequency-selective, long-range attractive forces is efficient at much longer distance than one proposed for linear dimension of the interacting macromolecules (100 – 1000Å) (Frohlich H. Nature 1970;228:1093). This frequency complementarity allows the long-range recognition and targeting (MOLECULAR SENSING) between interacting molecules, resulting in an increase of their productive collisions.
Physical base of the MOLECULAR SENSING
MOLECULAR SENSING is determined by the average quasi valence number (AQVN) and the electron-ion interaction potential (EIIP) (Veljkovic V. A theoretical approach to preselection of carcinogens and chemical carcinogenesis. Gordon & Breach, New York, 1981). These two fundamental physical properties of organic molecules are determined by the number of the valence electrons of constitutive atoms (Veljkovic and Slavic, Phys Rev Lett 1972;29:105, Veljkovic V. Phys Lett 1973;45A;41).
The MENDELEEV’S TABLE is only what is needed for study of the MOLECULAR SENSING between biological molecules.
INTERMOLECULAR INTERACTION IN BIOLOGICAL SYSTEMS
Ligand – Receptor
Antibody – Antigen
Enzyme – Substrate
Drug – Therapeutic Target
Recognition and Targeting between Interacting Molecules Interaction on Distances 5 – 1000Å)
Chemical Binding between Interacting Molecules (Interaction on Distances < 5Å)
Block Ligand – Target Binding
Block Molecular Sensing
Advantages of Therapeutic Approaches Which are Based on Modulation of the Molecular Sensing
- Resistance of pathogens and cancer cells to drugs and vaccines is less common because mutations which modulate the MOLECULAR SENSING are significantly less frequent than mutations which affect the molecular structure.
- Modulation of the MOLECULAR SENSING allows development of new generation of drugs and vaccines.
MOLECULAR SENSING – SUCCESS STORIES
Discovery of receptor binding site of HIV virus
In silico analysis of HIV envelope glycoprotein gp120 performed by the MOLECULAR SENSING approach in 1988, suggested that peptide V (NAKTIIVQL) in the second conserved domain (C2) of this protein is involved in the gp120/CD4 interaction . It is the first ever published result suggesting that this domain of HIV-1 gp120 (loop D) is involved in HIV/CD4 interaction.
Ten years later it was documented that the loop D plays an essential role in interaction between HIV and the CD4 receptor . Four of five residues (DNAKT) of the loop D, which directly bind to the receptor, are located within peptide V .
HIV broadly neutralizing antibodies (BNA)
Results obtained by MOLECULAR SENSING approach in 1992 suggested that peptide NTM within C2 domain of HIV gp120 encompasses the epitope which bind BNA [3,4].
In 2010, BNA VRC1, which bind epitope within peptide NTM, were identified . This BNA, which block gp120/CD4 interaction, currently represents the most promising immunotherapeutic for HIV disease.
HIV therapy by passive immunization
One HIV patient with the number of CD4 cells <200 who not reacts to existing therapy was treated with plasma enriched with natural autoantibodies that bind peptide NTM. After this treatment the number of patient's CD4 cells rose to 800 and stay stable above 400 for the next 5 years without any additional therapy [6,7]. Of note is that this patient 22 years after treatment is in good condition. Results from the first Phase 1 clinical trial of passive immunization of HIV patients were published on May 5 2016 . The essential part of the conformational epitope of the monoclonal antibody 3BNC117 which was used in this clinical trial overlaps the epitope of BNA used in clinical experiment described in Ref. 6.
The AIDS research based on the MOLECULAR SENSING revealed (i) that HIV envelope glycoprotein gp120 resembles some key features of human immunoglobulins [9-18] and (ii) that the main neutralization epitope of gp120 mimics some host self epitope [3,9,16,17,19]. These results strongly indicated that an effective and safe protective HIV vaccine is not possible [20-26].
Despite numerous promising results of laboratory, preclinical and clinical testing which were reported in last two decades, an efficient and safe HIV vaccine is not on the horizon.
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- Kwong et al. Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody. Nature 1998;393:648.
- Veljkovic et al. Spectral and sequence similarity between VIP and the second conserved region of HIV envelope glycoprotein gp120: possible consequences on prevention and therapy of AIDS., Biochem Biophys Res Commun1992;180:705.
- Veljkovic N., Metlas R., Prljic J., Manfredi R., Branch D., Stringer W. Veljkovic V. Antibodies reactive with C-terminus of the second conserved region of HIV-1gp120 as possible prognostic marker and therapeutic agent for HIV disease. J Clin Virol 2004;31S:39.
- Zhou et al. Structural base for broad and potent neutralization of HIV-1 by antibody VRC01. Science 2010;329:811.
- Veljkovic et al. The Role of Passive Immunization in HIV+ Patients: A Case Report. Chest 2001;120: 662.
- Veljkovic V., Metlas R. Application of VIP/NTM reactive natural antibodies in therapy of HIV disease. Int Rev Immunol 2004;23:437.
- Schoofs et al. Science 2016; DOI: 10.1126/science.aaf0972.
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- Veljkovic V., Metlas R., HIV and idiotypic T-cel regulation: another view., Immunol. Today 1992;15:39
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- Veljkovic V., Muller S., Kohler H. Does VaxGen hide the breakthrough infections. Lancet 2003;361:1743.
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- Veljkovic V., Kohler H., Muller S. Aids vaccine: state of the art at the beginning of the third millennium. Int Rev Immunol 2004;23:369.
- Veljkovic V., Prljic J., Veljkovic T. Safety and ethical consideration of AIDS vaccine. Int Rev Immunol 2004;23:465.
- Veljkovic V, Veljkovic N, Glisic S, Ho MW. AIDS vaccine: efficacy, safety, ethics. Vaccine 2008;26:3072.