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Comparative Study
. 2016 Oct 20;11(10):e0164970.
doi: 10.1371/journal.pone.0164970. eCollection 2016.

Structural Dynamics Investigation of Human Family 1 & 2 Cystatin-Cathepsin L1 Interaction: A Comparison of Binding Modes

Suman Kumar Nandy  1 , Alpana Seal  1
Affiliations
Comparative Study

Structural Dynamics Investigation of Human Family 1 & 2 Cystatin-Cathepsin L1 Interaction: A Comparison of Binding Modes

Suman Kumar Nandy et al. PLoS One. .

Abstract

Cystatin superfamily is a large group of evolutionarily related proteins involved in numerous physiological activities through their inhibitory activity towards cysteine proteases. Despite sharing the same cystatin fold, and inhibiting cysteine proteases through the same tripartite edge involving highly conserved N-terminal region, L1 and L2 loop; cystatins differ widely in their inhibitory affinity towards C1 family of cysteine proteases and molecular details of these interactions are still elusive. In this study, inhibitory interactions of human family 1 & 2 cystatins with cathepsin L1 are predicted and their stability and viability are verified through protein docking & comparative molecular dynamics. An overall stabilization effect is observed in all cystatins on complex formation. Complexes are mostly dominated by van der Waals interaction but the relative participation of the conserved regions varied extensively. While van der Waals contacts prevail in L1 and L2 loop, N-terminal segment chiefly acts as electrostatic interaction site. In fact the comparative dynamics study points towards the instrumental role of L1 loop in directing the total interaction profile of the complex either towards electrostatic or van der Waals contacts. The key amino acid residues surfaced via interaction energy, hydrogen bonding and solvent accessible surface area analysis for each cystatin-cathepsin L1 complex influence the mode of binding and thus control the diverse inhibitory affinity of cystatins towards cysteine proteases.

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Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Convergence of the properties of un-bound cathepsin L1s in solution.
A. Non-bonded electrostatic (i, iii) and VDW (ii, iv) energy profile in intra-protein (i, ii) and protein-water (iii, iv) interfaces. Color code is same for i-iv. B. RMSF analysis. C. Crystallographic and simulated B-factors. D. Protein dipole moment fluctuation densities. E. Radial distribution functions between backbone atoms of protein and water oxygen atoms.
Fig 2
Fig 2. Stability of the complexes.
RMSD of cathepsin L1-stefin/cystatin complexes (A) and ΔRMSF (RMSFbound—RMSFunbound) in stefins (B), cystatins (C) and cathepsin L1s (D).
Fig 3
Fig 3. Change in conformation of complexes after refinement.
Superimposed structures of refined complexes and corresponding docking outputs of cathepsin L1 complexes with (A) stefin A, (B) stefin B, (C) cystatin C, (D) cystatin D, (E) cystatin F, (F) cystatin M/E, (G) cystatin S, (H) cystatin SA, (I) cystatin SN. Refined structure was shown in green and docked output in cyan.
Fig 4
Fig 4. Participation of cathepsin L1 residues in cathepsin L1-stefin/cystatin interaction.
Residues always involve in interaction were colored in green, mostly took part were in purple and occurred seldom were in orange. cathepsin L1 (inset) and its 90˚ rotated were shown in picture. Residues with IE >10KJ/mol were considered for the representation.
Fig 5
Fig 5. Contribution of L1 loop in cathepsin L1-cystatin interaction.
Interaction energy profile of L1 loop of cystatin M/E (A), cystatin C (C), cystatin F (D) and alignment of L1 loop residues of cystatins (B). Error bars represent the estimated error in GROMACS calculation. Legends were same in A, C, D.
Fig 6
Fig 6. C-terminal interaction profile of stefin-cathepsin L1 complexes.
Potential energy of interaction of C-terminal region of Stefin A (A) and Stefin B (B) along with their C-terminal alignment.
See this image and copyright information in PMC

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