How do mutations and allosteric inhibitors modulate caspase-7 activity? A molecular dynamics study

Abstract

Caspases are members of a highly regulated aspartate-cysteine protease family which have important roles in apoptosis. Pharmaceutical studies focused on these molecules since they are involved in diseases such as cancer and neurodegenerative disorders. A small molecule which binds to the dimeric interface away from the binding site induces a conformational change that resembles the pro-caspase form of the molecule by shifting loop positions. The fluctuation mechanisms caused by mutations or binding of a ligand can explain the key mechanism for the function of that molecule. In this study, we performed molecular dynamics simulations on wild-type and mutated structures (C290N, R187M, Y223A, G188L and G188P) as well as allosterically inhibited structure (DICA-bound caspase-7) to observe the effects of the single mutations on intrinsic dynamics. The results show that previously known changes in catalytic activity upon mutations or allosteric ligand binding are reflected in corresponding changes in the global dynamics of caspase-7. Communicated by Ramaswamy H. Sarma.

Unraveling the Allosteric Communication Mechanisms in T-Cell Receptor–Peptide-Loaded Major Histocompatibility Complex Dynamics Using Molecular Dynamics Simulations: An Approach Based on Dynamic Cross Correlation Maps and Residue Interaction Energy Calculations

“…Construction of Dynamic Cross Correlation Matrices (DCCMs) from Principal Component Analysis (PCA). In order to investigate the difference in global motions of the selected structures and to identify the regions contributing to the anticipated difference, we applied principal component analysis (PCA) and constructed the dynamic cross correlation matrices (DCCMs) using the first 20 modes of motion following the same procedure employed in our previous studies 36,62 where a covariance matrix consisting of alpha-carbon positional fluctuations (C) was constructed using eq 1, where X is the coordinates of all alpha-carbon atoms of the protein with a dimension of 3N × 3N and ⟨X⟩ is the matrix of average positions of the alpha carbons along the equilibrium period of the trajectories.…”

Non-Apoptotic Caspase Activity Preferentially Targets a Novel Consensus Sequence Associated With Cytoskeletal Proteins in the Developing Auditory Brainstem

“…Relatively few amino acid substitutions are required to change the P4 subsite preference of caspase-3 and -7 from the negatively-charged aspartate (i.e. DXXD) to a preference for hydrophobic residues such as isoleucine and valine ( Hill et al, 2016 ; Bingöl et al, 2019 ; Grinshpon et al, 2019 ; Yao et al, 2021 ). Similar PTM-mediated changes to the caspase-3 active site may play a role in shifting the P4 consensus motif to IXXD, which we observed in the non-apoptotic chick auditory brainstem and which we predict is the most likely non-apoptotic consensus motif in humans.…”