SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape

Since 2020, the receptor-binding domain (RBD) of the spike protein of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been constantly mutating, producing most of the notable missense mutations in the context of “variants of concern”, probably in response to the vaccine-driven alteration of immune profiles of the human population. The Delta variant, in particular, has become the most prevalent variant of the epidemic, and it is spreading in countries with the highest vaccination rates, causing the world to face the risk of a new wave of the contagion. Understanding the physical mechanism responsible for the mutation-induced changes in the RBD’s binding affinity, its transmissibility, and its capacity to escape vaccine-induced immunity is the “urgent challenge” in the development of preventive measures, vaccines, and therapeutic antibodies against the coronavirus disease 2019 (COVID-19) pandemic. In this study, entropy–enthalpy compensation and the Gibbs free energy change were used to analyze the impact of the RBD mutations on the binding affinity of SARS-CoV-2 variants with the receptor angiotensin converting enzyme 2 (ACE2) and existing antibodies. Through the analysis, we found that the existing mutations have already covered almost all possible detrimental mutations that could result in an increase of transmissibility, and that a possible mutation in amino-acid position 498 of the RBD can potentially enhance its binding affinity. A new calculation method for the binding energies of protein–protein complexes is proposed based on the entropy–enthalpy compensation rule. All known structures of RBD–antibody complexes and the RBD–ACE2 complex comply with the entropy–enthalpy compensation rule in providing the driving force behind the spontaneous protein–protein docking. The variant-induced risk of breakthrough infections in vaccinated people is attributed to the L452R mutation’s reduction of the binding affinity of many antibodies. Mutations reversing the hydrophobic or hydrophilic performance of residues in the spike RBD potentially cause breakthrough infections of coronaviruses due to the changes in geometric complementarity in the entropy–enthalpy compensations between antibodies and the virus at the binding sites.

A Pareto-Improving Compensation Rule for Investment Treaties

ABSTRACT Investment treaties grant foreign investors legal rights to compensation for losses caused by certain host state conduct. Many states are reconsidering their involvement in these treaties because they perceive the risks to outweigh the benefits. We start from the normative premise that participation in investment treaties should benefit both ‘host’ and ‘home’ states. Using a law and economics approach, we model a variety of common fact scenarios that arise in investment treaty arbitration. Our modelling demonstrates that being party to an investment treaty does not necessarily benefit a host state. The objective of mutual benefits would be achieved if investment treaties were modified to provide only the minimum protection necessary to solve time inconsistency problems for the host state and, thereby, deter opportunistic conduct. The treaties should not place wider constraints on legal and policy change. Our specific proposal is that a state should only have to compensate the investor if it breaches or modifies the domestic legal regime governing the investment and that compensation should be the lesser of the investor’s loss and the host state’s gain from the host state not having had the new legal regime in place when the investment was made.

Das Kompensationsverbot bei der Steuerhinterziehung

§ 370 para. 4 sentence 3 of the German Fiscal Code (AO) is a highly controversial provision in terms of its purpose and scope of application. It is increasingly subject to constitutional criticism. The thesis shows to what extent the so-called prohibition of compensation rule (Kompensationsverbot) is still justified today. For this purpose, fundamental questions of tax evasion are examined and the case law on § 370 para. 4 sentence 3 AO is systematised and critically reviewed. Based on these findings, the paper identifies legal criteria for the applicability of the regulation and addresses the question of whether and when it also has effects beyond the scope of tax evasion. In the final part of the thesis, problems with respect to § 370 para. 4 sentence 3 AO arising from the new regulations on voluntary disclosure are examined. The work adresses scholars and practitioners of business and tax criminal law.

Macroscopic Random Telegraph Noise

It is proposed that macroscopic telegraph noise in superconductors is due to dynamic coexistence of ordered and disordered vortex phases (DP and OP) created by edge contamination mechanism. A novel, robust, with bias insensitive rates, macroscopic telegraph noise in low Ca-doped manganites is ascribed to the dynamic current redistribution assisted by a positive resistance feedback associated with Meyer–Neldel compensation rule.