Comparison of Different Combined Multiple Tunnel Complexes in Soft Soil under Seismic Vibrations

The resilience of underground tunnels has gained paramount importance recently, driven by the need to ensure the safety and functionality of critical transportation and infrastructure systems during seismic events. Underground tunnels are prone to severe damage when the soil condition is poor and located in a high seismic zone. While the behavior of individual tunnels has been extensively studied, the concept of multiple tunnels combined into a large tunnel complex is relatively new, with limited available research focusing on rectangular-shaped tunnel complexes and requiring a more detailed examination. This study parametrically analyzes two novel and unconventional structures in soft soil, i.e., twin and triple tunnel complexes resulting from the combination of closely spaced circular twin and triple individual tunnels. Seismic records from Coyote (US, 1979), Kobe (Japan, 1995), and Kocaeli (Turkey, 1999) have been used to determine the produced surface displacements, tunnel distortions, lateral stresses on the tunnel structures, and the induced seismic forces, including thrusts, shear forces, and bending moments. The results are then compared with the conventional rectangular-shaped tunnel complex, which is also analyzed under the same conditions. The comparison shows that the twin and triple tunnel complexes are comparatively better seismic performers than the conventional rectangular tunnel complex, with reduced ground displacements produced, lesser incurred structural distortions, experienced lateral stresses, and induced seismic forces. Doi: 10.28991/CEJ-2023-09-12-01 Full Text: PD

A community effort in SARS-CoV-2 drug discovery.

peer reviewedThe COVID-19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small-molecule drugs that are widely available, including in low- and middle-income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the "Billion molecules against Covid-19 challenge", to identify small-molecule inhibitors against SARS-CoV-2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find 'consensus compounds'. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding-, cleavage-, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS-CoV-2 treatments.R-AGR-3826 - COVID19-14715687-CovScreen (01/06/2020 - 31/01/2021) - GLAAB Enric

Computing the Role of Near Attack Conformations in an Enzyme-Catalyzed Nucleophilic Bimolecular Reaction

Near attack conformations (NACs) are conformations extending from the ground state (GS) that lie on the transition path of a chemical reaction. Here, we develop a method for computing the thermodynamic contribution to catalysis due to NAC formation in bimolecular reactions, within the limit of a classical molecular dynamics force field. We make use of the Bürgi–Dunitz theory applied to large-scale unbiased all-atom ensemble molecular dynamics simulations. We apply this to HIV-1 protease peptide hydrolysis, known to achieve a rate enhancement of ∼10¹¹ (Δ<i>G</i>_cat^⧧ ∼ 15 kcal/mol) over the uncatalyzed bimolecular reaction (Δ<i>G</i>_non^⧧ ∼ 30 kcal/mol). The ground state consists of a nucleophilic water molecule bound to an octapeptide substrate in the active site. We first observe multiple and reversible binding of a nucleophilic water molecule into the active site giving a free energy of binding of Δ<i>G</i> = −1 kcal/mol to form the GS. The free energy barriers for catalyzed and uncatalyzed NAC formation are both equivalent: Δ<i>G</i>_NAC^⧧ = 4.6 kcal/mol, constituting ∼30% and ∼15% of the overall barriers, respectively. Therefore, not only does adoption of NACs only account for minor progress along the transition path in both catalyzed and uncatalyzed reactions, but there is no preferential formation of them in the catalyzed reaction. Analysis of the catalytic hydrogen bond network reveals interactions that stabilize the GS; however, subsequent NAC formation does not preferentially favor any of the possible hydrogen bond configurations. This supports the view that the catalytic power of HIV-1 protease is not due to NAC formation