Computational design of proteins is a relatively new field, where scientists search the enormous sequence space for sequences that can fold into desired structure and perform desired functions. With the computational ...Computational design of proteins is a relatively new field, where scientists search the enormous sequence space for sequences that can fold into desired structure and perform desired functions. With the computational approach, proteins can be designed, for example, as regulators of biological processes, novel enzymes, or as biotherapeutics. These approaches not only provide valuable information for understanding of sequence-structure-function relations in proteins, but also hold promise for applications to protein engineering and biomedical research. In this review, we briefly introduce the rationale for computational protein design, then summarize the recent progress in this field, including de novo protein design, enzyme design, and design of protein-protein interactions. Challenges and future prospects of this field are also discussed.展开更多
Matrix-assisted laser desorption/ionization(MALDI)mass spectrometry(MS)plays an indispensable role in analyzing protein covalent structures.The reliable identification of amino acid residues and modifications relies o...Matrix-assisted laser desorption/ionization(MALDI)mass spectrometry(MS)plays an indispensable role in analyzing protein covalent structures.The reliable identification of amino acid residues and modifications relies on the mass accuracy,which is highly dependent on calibration.However,the accuracy provided by the currently available calibrants still needs further improvement in terms of compatibility with multiple tandem MS modes or ion polarity modes,calibratable range,and minimizing suppression of and interference with analyte signals.Here aiming at developing a versatile calibrant to solve these problem,we designed a synthetic peptide format of calibrant R_x(GDP_n)_m(referred to as“Gly-Asp-Pro,GDP”)according to the chemical natures of amino acids and polypeptide fragmentation rules in tandem MS.With four types of amino acid residues selected and arranged through rational designs,a GDP peptide produces highly regulated fragments that give rise to evenly spaced signals in each tandem MS mode and is compatible with both positive and negative ion modes.In internal calibration,its regulated fragmentation pattern minimizes interference with analyte signals,and using a single peptide as the input minimizes suppression of the analyte signals.As demonstrated by analyses of proteins including monoclonal antibody and Aβ-42,these features allowed significant increase of the mass accuracy and precision,which improved sequence coverage and sequence resolution in sequence analyses(including de novo sequencing).This rational design strategy may also inspire further development of synthetic calibrants that benefit structural analysis of biomolecules.展开更多
Transmembrane nanopores are structurally stable and biocompatible, and have various applications in molecular sensing and selective transport. The relationship between the function and structure is crucial for transme...Transmembrane nanopores are structurally stable and biocompatible, and have various applications in molecular sensing and selective transport. The relationship between the function and structure is crucial for transmembrane nanopores, but it is still challenging to design and precisely tune the structure of conventional protein nanopores from scratch, albeit of abundant previous work on natural and bioengineered transmembrane protein nanopores. Therefore, numerous types of artificial transmembrane nanopores that can be de novo designed are rapidly under development, such as molecular nanopores, peptide nanopores, and DNA origami nanopores. In this review, we compare different building blocks of “bottom-up” built nanopores in terms of construction methods, structures and applications, and also describe important advances in de novo designed proteins from the perspective of theoretical simulations as well as an outlook for artificial intelligence-assisted nanopore design.展开更多
蛋白质的三维结构是研究其生物功能及活性机理的基础.为了提高蛋白质结构的预测精度,在进化计算的框架下,提出一种接触图辅助的过程重采样蛋白质构象空间优化算法(Contact Map-assistedProcess Resampling Protein Conformation Space O...蛋白质的三维结构是研究其生物功能及活性机理的基础.为了提高蛋白质结构的预测精度,在进化计算的框架下,提出一种接触图辅助的过程重采样蛋白质构象空间优化算法(Contact Map-assistedProcess Resampling Protein Conformation Space Optimization Algorithm,CM PR). CM PR算法基于残基接触图设计打分模型,用于选择构象以构建过程片段库,使用基于过程重采样策略的片段组装技术执行变异操作,残基接触先验知识和种群进化过程统计知识辅助采样,可以增强近天然态构象区域的搜索能力,提高蛋白质结构预测精度.在12个测试蛋白上的实验结果表明,所提方法具有良好的近天然态构象采样能力和较高的预测精度.展开更多
预测蛋白质结构对药物设计和疾病诊断有着重要的科学意义.针对蛋白质结构从头预测问题,在进化算法框架下,提出一种距离和疏水模型辅助的蛋白质结构预测方法(Distance and Hydrophobic Model-assisted Protein Structure Prediction Meth...预测蛋白质结构对药物设计和疾病诊断有着重要的科学意义.针对蛋白质结构从头预测问题,在进化算法框架下,提出一种距离和疏水模型辅助的蛋白质结构预测方法(Distance and Hydrophobic Model-assisted Protein Structure Prediction Method,DHM A).首先根据亲疏水性构建氨基酸的回转半径来指导构象空间采样,达到提高搜索效率的目的;然后,利用距离谱构建距离分布估计模型和疏水概率模型,指导种群更新,缓解能量函数不精确带来的误差.在10个测试蛋白的预测结果表明,DHM A具有良好的搜索性能和预测精度,是一种有效的蛋白质结构预测方法.展开更多
基金supported by the National Basic Research Program of China(Grant No.2015CB910300)the National High Technology Research and Development Program of China(Grant No.2012AA020308)the National Natural Science Foundation of China(Grant No.11021463)
文摘Computational design of proteins is a relatively new field, where scientists search the enormous sequence space for sequences that can fold into desired structure and perform desired functions. With the computational approach, proteins can be designed, for example, as regulators of biological processes, novel enzymes, or as biotherapeutics. These approaches not only provide valuable information for understanding of sequence-structure-function relations in proteins, but also hold promise for applications to protein engineering and biomedical research. In this review, we briefly introduce the rationale for computational protein design, then summarize the recent progress in this field, including de novo protein design, enzyme design, and design of protein-protein interactions. Challenges and future prospects of this field are also discussed.
基金supported by grants from the National Natural Science Foundation of China(No.21974069)Open Fund Programs of Shenzhen Bay Laboratory(No.SZBL2020090501001)。
文摘Matrix-assisted laser desorption/ionization(MALDI)mass spectrometry(MS)plays an indispensable role in analyzing protein covalent structures.The reliable identification of amino acid residues and modifications relies on the mass accuracy,which is highly dependent on calibration.However,the accuracy provided by the currently available calibrants still needs further improvement in terms of compatibility with multiple tandem MS modes or ion polarity modes,calibratable range,and minimizing suppression of and interference with analyte signals.Here aiming at developing a versatile calibrant to solve these problem,we designed a synthetic peptide format of calibrant R_x(GDP_n)_m(referred to as“Gly-Asp-Pro,GDP”)according to the chemical natures of amino acids and polypeptide fragmentation rules in tandem MS.With four types of amino acid residues selected and arranged through rational designs,a GDP peptide produces highly regulated fragments that give rise to evenly spaced signals in each tandem MS mode and is compatible with both positive and negative ion modes.In internal calibration,its regulated fragmentation pattern minimizes interference with analyte signals,and using a single peptide as the input minimizes suppression of the analyte signals.As demonstrated by analyses of proteins including monoclonal antibody and Aβ-42,these features allowed significant increase of the mass accuracy and precision,which improved sequence coverage and sequence resolution in sequence analyses(including de novo sequencing).This rational design strategy may also inspire further development of synthetic calibrants that benefit structural analysis of biomolecules.
基金the support from the National Natural Science Foundation of China(21974123)the Natural Science Foundation of Zhejiang Province(LR20B050002)the Fundamental Research Funds for the Central Universities(2022KYY5060320001)。
文摘Transmembrane nanopores are structurally stable and biocompatible, and have various applications in molecular sensing and selective transport. The relationship between the function and structure is crucial for transmembrane nanopores, but it is still challenging to design and precisely tune the structure of conventional protein nanopores from scratch, albeit of abundant previous work on natural and bioengineered transmembrane protein nanopores. Therefore, numerous types of artificial transmembrane nanopores that can be de novo designed are rapidly under development, such as molecular nanopores, peptide nanopores, and DNA origami nanopores. In this review, we compare different building blocks of “bottom-up” built nanopores in terms of construction methods, structures and applications, and also describe important advances in de novo designed proteins from the perspective of theoretical simulations as well as an outlook for artificial intelligence-assisted nanopore design.
文摘蛋白质的三维结构是研究其生物功能及活性机理的基础.为了提高蛋白质结构的预测精度,在进化计算的框架下,提出一种接触图辅助的过程重采样蛋白质构象空间优化算法(Contact Map-assistedProcess Resampling Protein Conformation Space Optimization Algorithm,CM PR). CM PR算法基于残基接触图设计打分模型,用于选择构象以构建过程片段库,使用基于过程重采样策略的片段组装技术执行变异操作,残基接触先验知识和种群进化过程统计知识辅助采样,可以增强近天然态构象区域的搜索能力,提高蛋白质结构预测精度.在12个测试蛋白上的实验结果表明,所提方法具有良好的近天然态构象采样能力和较高的预测精度.
文摘预测蛋白质结构对药物设计和疾病诊断有着重要的科学意义.针对蛋白质结构从头预测问题,在进化算法框架下,提出一种距离和疏水模型辅助的蛋白质结构预测方法(Distance and Hydrophobic Model-assisted Protein Structure Prediction Method,DHM A).首先根据亲疏水性构建氨基酸的回转半径来指导构象空间采样,达到提高搜索效率的目的;然后,利用距离谱构建距离分布估计模型和疏水概率模型,指导种群更新,缓解能量函数不精确带来的误差.在10个测试蛋白的预测结果表明,DHM A具有良好的搜索性能和预测精度,是一种有效的蛋白质结构预测方法.
