Affinity improvement of proteins, including antibodies, by computational chemistry broadly relies on physics-based energy functions coupled with refinement. However, achieving significant enhancement of binding affinity (>10-fold) remains a challenging exercise, particularly for cross-reactive antibodies. We describe here an empirical approach that captures key physicochemical features common to antigen-antibody interfaces to predict proteinprotein interaction and mutations that confer increased affinity. We apply this approach to the design of affinity-enhancing mutations in 4E11, a potent cross-reactive neutralizing antibody to dengue virus (DV), without a crystal structure. Combination of predicted mutations led to a 450-fold improvement in affinity to serotype 4 of DV while preserving, or modestly increasing, affinity to serotypes 1-3 of DV. We show that increased affinity resulted in strong in vitro neutralizing activity to all four serotypes, and that the redesigned antibody has potent antiviral activity in a mouse model of DV challenge. Our findings demonstrate an empirical computational chemistry approach for improving protein-protein docking and engineering antibody affinity, which will help accelerate the development of clinically relevant antibodies. (1). Engineering improved affinity and specificity of these compounds can augment their potency and safety while decreasing required dosages. Production of antibodies with binding properties of interest typically relies on methods involving screening large numbers of clones generated by the immune system or by mutant libraries (2, 3). Alternatively, computer-based design offers the potential to rationally mutate available antibodies for improved properties, including enhanced affinity and specificity to target antigens. Recently, several successful examples of antibody affinity improvement by computational methods using physical modeling with energy minimization have been described (4-6). However, such approaches require a 3D structure of the antibody-antigen complex and rarely result in affinity gains greater than 10-fold. Further, these approaches are sensitive to precise atomic coordinates, rendering them inapplicable to computer-generated models. More significantly, enhancement of affinity in the context of an antibody that recognizes multiple antigens (i.e., crossreactive) remains a particular challenge.Dengue is the most medically relevant arboviral disease in humans, with an estimated 3.6 billion people at risk for infection. More than 200 million infections of dengue virus (DV) are estimated to occur globally each year (7). The incidence, geographical outreach, and number of severe disease cases of dengue are increasing (8, 9), making DV of increasing concern as a human pathogen. The complex of DVs is composed of four distinct serotypes (designated DV1-4) (10), which vary from one another at the amino acid level by 25-40%. The sequence and antigenic variability of DVs have challenged efforts to develop an effective vaccine or therapeutic against a...
To monitor study and analyze the social public service quality is conducive to promote the construction of a service-oriented government that is satisfactory to the people. In this paper, third-party quality monitoring was conducted in 14 cities of Liaoning Province from 11 public service fields such as living environment, public transportation, infrastructure, medical and health care, public security, culture and sports, compulsory education, pension service, employment service, social security and administrative convenience. The results showed that the public’s satisfaction with social security, compulsory education, living environment, public security and employment services was low, which needed to be paid attention to and further improved by Liaoning Provincial Government.
This paper explores the difficulties of building a service-oriented government by taking the evaluation results of public service satisfaction of Guizhou province in 2019 as an example. This paper finds that building a service-oriented government is the process of improving the quality of public service in an all-round way. With the steady improvement of the public service quality in China, the public’s expectation of the public service quality has been improved by changing from the original “yes or no” to the current “good or not”. In order to speed up the construction of service-oriented government, government departments should pay attention to the change of public demand and take the comfort, richness and transparency of public service as the key points of quality improvement.
This paper explores the level of high-quality economic development in the Tibet Autonomous Region in 2019 by using the quantitative method and taking the public satisfaction of government quality work as the path. The article holds that the Tibet Autonomous Region's economy is developing at a high speed, but the level of high-quality economic development is still at a relatively satisfactory level and there is still much room for improvement. Generally speaking, the level of environmental quality satisfaction is higher, followed by the level of service quality, engineering quality and product quality satisfaction, and the level of quality consciousness satisfaction is lower. In addition to the structural factors such as backward production capacity, the micro-factors such as product qualification rate and engineering safety have a great influence on the high-quality development of Tibet.
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