Abstract

BACE-1 is the β-secretase responsible for the initial amyloidogenesis in Alzheimer’s disease, catalyzing hydrolytic cleavage of substrate in a pH-sensitive manner. The catalytic mechanism of BACE-1 requires water-mediated proton transfer from aspartyl dyad to the substrate, as well as structural flexibility in the flap region. Thus, the coupling of protonation and conformational equilibria is essential to a full in silico characterization of BACE-1. In this work, we perform constant pH replica exchange molecular dynamics simulations on both apo BACE-1 and five BACE-1-inhibitor complexes to examine the effect of pH on dynamics and inhibitor binding properties of BACE-1. In our simulations, we find that solution pH controls the conformational flexibility of apo BACE-1, whereas bound inhibitors largely limit the motions of the holo enzyme at all levels of pH. The microscopic pKa values of titratable residues in BACE-1 including its aspartyl dyad are computed and compared between apo and inhibitor-bound states. Changes in protonation between the apo and holo forms suggest a thermodynamic linkage between binding of inhibitors and protons localized at the dyad. Utilizing our recently developed computational protocol applying the binding polynomial formalism to the constant pH molecular dynamics (CpHMD) framework, we are able to obtain the pH-dependent binding free energy profiles for various BACE-1-inhibitor complexes. Our results highlight the importance of correctly addressing the binding-induced protonation changes in protein-ligand systems where binding accompanies a net proton transfer. This work comprises the first application of our CpHMD-based free energy computational method to protein-ligand complexes and illustrates the value of CpHMD as an all-purpose tool for obtaining pH-dependent dynamics and binding free energies of biological systems.Quantum Key Distribution with Qubit Pairs An in silico annotated drug discovery interactive approach for the depletion of tumor-associated macrophages by a computer-aided designed canditate druggable Toll-like receptor (Pam2IDG) peptide-domain targeted by a pharmacophoric mimetic agonistic agent.Conformational Dynamics and Binding Free Energies of Inhibitors of BACE-1: From the Perspective of Protonation Equilibria.We propose a new Quantum Key Distribution method in which Alice sends pairs of qubits to Bob; each is in one of four possible states. Bob uses one qubit to generate a secure key and the other to generate an auxiliary key. For each pair he randomly decides which qubit to use for which key. The auxiliary key has to be added to Bob’s secure key in order to match Alice’s secure key. This scheme provides an additional layer of security over the standard BB84 protocol.Keywords: Quantum Key Distribution, Quantum Cryptography1. It has been previosuly reported that lipopeptides can be used to elicit cytotoxic T lymphocyte (CTL) responses against viral diseases and cancer. In previous scientific projects, it has also been determined that mono-palmitoylated peptides can enhance anti-tumor responses in the absence of adjuvant activity. To investigate whether di-palmitoylated peptides with TLR2 agonist activity are able to induce anti-tumor immunity, it was previously synthesized a di-palmitic acid-conjugated long peptide that contains a murine CTL epitope of HPV E749-57 (Pam2IDG). Pam2IDG stimulated the maturation of bone marrow-derived dendritic cells (BMDCs) through TLR2/6. After immunization, Pam2IDG induced higher levels of T cell responses than those obtained with its non-lipidated counterpart (IDG). Here, we present a novel approach based on GRID molecular interaction fields and the derivative peptide mimicking rationally drug discovery method that has been previously utilized, which may provides a common reference to compare both small molecule ligands and conserved fragment-peptide targeting. Unlike classical pharmacophore elucidation approaches that extract simplistic molecular features, determine those which are common across the data set, and use these features to align the structures and subsequently extracts the common interacting features in terms of their molecular interaction fields, pseudofields, and atomic points, representing the common pharmacophore as a more comprehensive pharmacophoric pseudomolecule. Our fragment-ligand based drug discovery approach is applied to a number of data sets to investigate performance in terms of reproducing the X-ray crystallography-based alignment, in terms of its discriminatory ability when applied to virtual screening and also to illustrate its ability to explain alternative binding modes. As a result we discovered for the first time the GENEA-Tollarepomir-5579, an in silico annotated drug discovery interactive approach of Inhibitors of BACE-1 of tumor-associated macrophages by a computer-aided designed canditate druggable Toll-like receptor (Pam2IDG) peptide-domain targeted by a pharmacophoric mimetic agonistic agent by Conformational Dynamics Quantum Key Distribution with Qubit Pairs and Binding Free Energies From the Perspective of Protonation Equilibria.

Keywords

Toll-likereceptor;agonist-conjugated;peptide-mimetic;pharmacophoric;multi-targeted, Quantum Key Distribution;Qubit Pairs; in silico; annotated drug discovery; interactive approach; tumor-associated macrophages; computer-aided; druggable; Toll-like receptor; (Pam2IDG) peptide-domain; Conformational Dynamics; Binding Free Energies; Inhibitors of BACE-1; From the Perspective of Protonation Equilibria; Conformational