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Cardiotoxins: Functional Role of Local Conformational Changes
Anastasia G Konshina1, Nikolay A Krylov1,2, Roman G Efremov1
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences , 16/10 Miklukho-Maklaya str., 117997 GSP, Moscow V-437, Russia.
Journal of Chemical Information and Modeling
|October 21, 2017
Summary
Local protein dynamics in cardiotoxins (CTs) from snake venom influence their membrane interactions. Specific residue pairs, like K5/L6, alter hydrophobic patterns, enabling a two-stage CT-membrane binding mechanism.
Area of Science:
- Biochemistry
- Structural Biology
- Toxicology
Background:
- Cardiotoxins (CTs) are basic proteins from snake venom known for membrane activity.
- Their exact cell damage mechanisms are poorly understood.
- Understanding structure-function relationships requires detailed knowledge of CT spatial organization and dynamics.
Purpose of the Study:
- To explore large-scale dihedral angle transitions in CTs using molecular dynamics (MD).
- To investigate the relationship between local conformational dynamics and CT membrane activity.
- To elucidate the structure-function relationships of CTs.
Main Methods:
- Long-term molecular dynamics (MD) simulations in explicit water for three CTs.
- Analysis of MD-derived distributions of backbone torsion angles.
- Comparison of CT hydrophobic pattern sizes with model membrane dimensions.
Main Results:
- Large-amplitude dihedral angle transitions were observed in functionally important loop I residues.
- The K5/L6 residue pair was identified as a "hot spot" that perturbs CT hydrophobic patterns.
- CT hydrophobic pattern sizes matched dimensions on model membranes, suggesting a two-stage binding mechanism.
Conclusions:
- Local conformational dynamics, particularly in loop I, significantly impact CT functional activity.
- Specific "hot spots" like K5/L6 tune the CT-membrane binding site.
- A two-stage mechanism for CT-membrane binding was proposed based on structural dynamics and experimental data.
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