Protein Predictive Modeling and Simulation of Mutations of Presenilin-1 Familial Alzheimer’s Disease on the Orthosteric Site

Abstract

Alzheimer’s disease pathology is characterized by β-amyloid plaques and neurofibrillary tangles. Amyloid precursor protein is processed by β and γ secretase, resulting in the production of β-amyloid peptides with a length ranging from 38 to 43 amino acids. Presenilin 1 (PS1) is the catalytic unit of γ-secretase, and more than 200 PS1 pathogenic mutations have been identified as causative for Alzheimer’s disease. A complete monocrystal structure of PS1 has not been determined so far due to the presence of two flexible domains. We have developed a complete structural model of PS1 using a computational approach with structure prediction software. Missing fragments Met1-Glut72 and Ser290-Glu375 were modeled and validated by their energetic and stereochemical characteristics. Then, with the complete structure of PS1, we defined that these fragments do not have a direct effect in the structure of the pore. Next, we used our hypothetical model for the analysis of the functional effects of PS1 mutations Ala246GLu, Leu248Pro, Leu248Arg, Leu250Val, Tyr256Ser, Ala260Val, and Val261Phe, localized in the catalytic pore. For this, we used a quantum mechanics/molecular mechanics (QM/MM) hybrid method, evaluating modifications in the topology, potential surface density, and electrostatic potential map of mutated PS1 proteins. We found that each mutation exerts changes resulting in structural modifications of the active site and in the shape of the pore. We suggest this as a valid approach for functional studies of PS1 in view of the possible impact in substrate processing and for the design of targeted therapeutic strategies.

Mechanism of Tripeptide Trimming of Amyloid β-Peptide 49 by γ-Secretase

“…Recently reported cryo-EM structures of γ-secretase bound to Notch and APP substrates provided valuable insights into the structural basis of substrate recognition of the enzyme. , However, artificial structural constraints were included that could affect the enzyme–substrate interactions. Molecular dynamics (MD) simulations have proven useful in understanding the structural dynamics of γ-secretase, notably the enzyme–substrate interactions, including many previous studies. − Recently, we computationally restored the wild-type (WT) enzyme–substrate costructure and applied all-atom simulations using the Gaussian accelerated molecular dynamics (GaMD) method to build the first dynamic model of γ-secretase activation . GaMD is an enhanced sampling technique that works by adding a harmonic boost potential to smooth the potential energy surface and reduce system energy barriers .…”

Structural Protein Effects Underpinning Cognitive Developmental Delay of the PURA p.Phe233del Mutation Modelled by Artificial Intelligence and the Hybrid Quantum Mechanics–Molecular Mechanics Framework

“…To better quantify the Phe233 mutation effects at the atomic functional resolution, we applied a combination of hybrid quantum chemistry theory (focusing on the deletion vicinity region) and molecular mechanics force field theory (applied to other PURA regions far from the vicinity of the Phe233 deletion). Both theories amalgamated in the QM/MM semiempirical method (preferred for macromolecular systems) [ 44 , 45 , 46 , 47 , 48 ]. We used the model’s parameterization with the Z matrix of connectivity and experimental data derived from empirical crystallographic studies, focusing on those targeting the Phe233del position.…”

GS-SMD server for steered molecular dynamics of peptide substrates in the active site of the γ-secretase complex

“…recent papers ( 11–15 ), including theoretical calculations. The studies also involve the effect of mutations in GS, mostly in PS-1 being the catalytic core of GS complex, since it contains most of the known AD mutations ( 16 , 17 ). Nearly 300 causative mutations represent ∼90% of all mutations associated with an aggressive AD form (Figure 1C ).…”