Abstract
Many studies have provided evidence suggesting that caspases not only contribute to the neurodegeneration associated with Alzheimer’s disease (AD) but also play essential roles in promoting the underlying pathology of this disease. Studies regarding the caspase inhibition draw researchers’ attention through time due to its therapeutic value in the treatment of AD. In this work, we apply the “Movable Type” (MT) free energy method, a Monte Carlo sampling method extrapolating the binding free energy by simulating the partition functions for both free-state and bound-state protein and ligand configurations, to the caspase-inhibitor binding affinity study. Two test benchmarks are introduced to examine the robustness and sensitivity of the MT method concerning the caspase inhibition complexing. The first benchmark employs a large-scale test set including more than a hundred active inhibitors binding to caspase-3. The second benchmark includes several smaller test sets studying the relative binding free energy differences for minor structural changes at the caspase-inhibitor interaction interfaces. Calculation results show that the RMS errors for all test sets are below 1.5 kcal/mol compared to the experimental binding affinity values, demonstrating good performance in simulating the caspase-inhibitor complexing. For better understanding the protein-ligand interaction mechanism, we then take a closer look at the global minimum binding modes and free-state ligand conformations to study two pairs of caspase-inhibitor complexes with (1) different caspase targets binding to the same inhibitor, and (2) different polypeptide inhibitors targeting the same caspase target. By comparing the contact maps at the binding site of different complexes, we revealed how small structural changes affect the caspase-inhibitor interaction energies. Overall, this work provides a new free energy approach for studying the caspase inhibition, with structural insight revealed for both free-state and bound-state molecular configurations.
Highlights
Alzheimer disease (AD) is a neurodegenerative disorder characterized by the neuronal and synaptic loss as well as the accumulation of β-amyloid plaques and neurofibrillary tangles (NFTs) within selective brain regions
The results could provide theoretical support to proceed further study the feasibility of applying the Movable Type Free Energy Method to design caspase ligand inhibitors, which are closely related to Alzheimer’s disease
A relatively large test set was studied to obtain a general picture of the Movable Type” (MT) method’s performance to differentiate the binding affinities of a large variety of ligand structures binding to the caspase-3 protein target
Summary
Alzheimer disease (AD) is a neurodegenerative disorder characterized by the neuronal and synaptic loss as well as the accumulation of β-amyloid plaques and neurofibrillary tangles (NFTs) within selective brain regions. A family of serine-aspartyl proteases, are involved in the initiation and execution of apoptosis. They are known to exist in our cells as inactive precursors which kill the cell once activated and lead to the proteolytic cleavage of several neuronal proteins including tau, APP, presenilin (PS1, PS2), actin, fodrin, etc. Many research results have been published to elucidate the correlation between AD pathogenesis and caspases family members, mostly caspases-2, 3, 6, 7, 8 and 9 [2,12,13,14,15,16,17,18,19] These studies suggest that preventing caspase activation may be a promising therapeutic for the treatment of AD. Various caspase inhibitors, including small molecules, peptidomimetic and peptide compounds, have been designed to study the relationship between caspases and other factors involved in apoptosis
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