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Interactions of β-sheet cardiotoxins with implicit membrane

Another intriguing question which could be addressed to the utilization of the implicit membrane model is interaction of β-structural proteins with the membrane. For these purpose cardiotoxins from snake venom were chosen as objects of investigation.

Cardiotoxins (cytotoxins, CTXs) are subdivided into two classes: P-type and S-type:

Properties of two CTX from different classes were explored via combination of molecular dynamics in explicit water, MC simulations in implicit membrane and analysis of their hydrophobic properties.

Molecular dynamics in water

Purpose: Estimation of conformational mobility of CTXs in water environment.

Results:

High conformational mobility of loops I and II; Adoption of “Ω-like” shape of loop II is independent of starting models: X-ray and NMR structures of CTX A5 (P-type) and two NMR structures of CTX A3 (P-type).

Monte Carlo simulation (with implicit lipid bilayer model)

Purpose: Assessment of mode of CTX’s binding with the membrane.

Results:

Mode of binding depends on the CTX type. P-type cardiotoxins interacts with the membrane mach stronger.

Distribution of molecular hydrophobicity potential (MHP) on molecular surface of membrane-bound state of CTX A5

Purposes:

• Characterization of membrane-bound state;
• Exploration of mode of binding.

Results:
MHP calculation (MHP is projected on the planes A and A’):

Typical hydrophobicity pattern on toxin’s molecular surface:

Conclusions:

• Toxins do not change their overall spatial structures upon insertion into membrane;
• P-type CTXs bind to lipid bilayer with the hydrophobic tips of loops I–III;
• S-type CTX interacts with model membrane only via loop I;
• The protein’s mode of membrane binding mainly depends on local hydrophobic and conformational properties of CTXs.

Read more about the molecular hydrophobicity potential (MHP).

(Authors: A. Konshina, P. Volynsky, R. Efremov)

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