Computational Structure-Based Protein Design
基于计算结构的蛋白质设计
基本信息
- 批准号:9915930
- 负责人:
- 金额:$ 35.4万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-04-15 至 2022-04-30
- 项目状态:已结题
- 来源:
- 关键词:AccelerationAddressAffinityAlgorithm DesignAlgorithmic SoftwareAlgorithmsAmino Acid SequenceAntibodiesAreaBasic ScienceBindingBiochemicalBiologicalCandida glabrataCapsid ProteinsCell ProliferationCellsClinicalClinical TrialsClinical Trials DesignCombinatorial OptimizationCommunity-Acquired InfectionsComputer softwareCrystallizationCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDesigner DrugsDevelopmentDisease ResistanceDrug resistanceEscherichia coliFoundationsFutureGenesGlycoproteinsGrantGuanosine Triphosphate PhosphohydrolasesHIVHIV AntibodiesHIV envelope proteinHIV resistanceHIV therapyHIV-1HumanInfluenzaInvestigationKRAS2 geneLaboratoriesLeadLigandsMalariaMalignant NeoplasmsMathematicsMeasuresMedical ResearchMembraneMembrane ProteinsMethodologyMethodsModelingMolecularMolecular ConformationMutateMutationPancreatic Ductal AdenocarcinomaPassive ImmunizationPeptidesPharmaceutical PreparationsPharmacologyProcessProtein EngineeringProteinsProto-OncogenesResistanceSideSignal TransductionSiteSpecificitySpeedStructureSymptomsSystemTestingTherapeuticThermodynamicsTimeTuberculosisVancomycin resistant enterococcusVertebral columnantibiotic designbasecystic fibrosis patientsdesignenv Gene Productsenzyme activityexperimental studyflexibilityimmunogenicimprovedin vivoinhibitor/antagonistmethicillin resistant Staphylococcus aureusmodel designmolecular mechanicsmolecular modelingmutantneutralizing antibodynew therapeutic targetnovelnovel therapeuticsopen sourcepathogenprospectiveprotein protein interactionprotein structureprotein transportresistance mutationresponsesoftware developmentstructured datasuccessunnatural amino acids
项目摘要
Project Summary. Computational structure-based protein design is a transformative field with exciting
prospects for advancing both basic science and translational medical research. My laboratory has developed
new protein design algorithms and used them to predict MRSA resistance to new antibiotics; design a broadly
neutralizing antibody VRC07-523LS against HIV with unprecedented breadth and potency that is now in
clinical trials; design protein-peptide interactions to treat cystic fibrosis; perform antigenicity-guided structural
design of HIV gp140 envelope protein (Env) trimer constructs to delineate mechanism and fix conformation;
and design a new antigenic membrane-bound membrane proximal external region (MPER) trimer for
examining immunogenic responses to the HIV viral coat protein gp41. Central to protein design methodology
is the need to optimize the amino acid sequence, placement of side chains, and backbone conformations in
protein structures. By developing advanced search and scoring algorithms for combinatorial optimization of
protein and ligand structure and sequence, we showed that desired structure, affinity, and activity can be
designed by (a) modeling improved molecular flexibility and (b) exploiting ensembles of structures for accurate
predictions. Our suite of algorithms has mathematical guarantees on the solution quality (up to the accuracy of
the input model, which includes the initial structures, molecular flexibility to be modeled, and an empirical
molecular mechanics energy function). Specifically, our algorithms guarantee to compute the global minimum
energy conformation (GMEC), a gap-free list of sequences and structures in order of predicted energy, and a
provably-good approximation to the binding affinity by bounding partition functions over molecular ensembles.
We propose to build on our foundation of protein design algorithms, called OSPREY, and apply them in areas
of biochemical and pharmacological importance. We will (1) predict future resistance mutations in protein
targets of novel drugs; (2) design inhibitors of protein:protein interactions to target today’s “undruggable”
proteins; and (3) use OSPREY to redesign and improve broadly neutralizing HIV antibodies. Improvements to
our protein design algorithms will be implemented to improve accuracy and scope, and we will advance the
state of the art in protein design by making algorithmic and modeling improvements to accomplish the Aims (1-
3) above, including: the modeling of more protein/ligand flexibility and improved energy functions during large-
scale design; new combinatorial optimization and energy-fitting methods to accelerate the design search; and
design of affinity and specificity using novel multi-state design algorithms that model thermodynamic molecular
ensembles. We will test our design predictions prospectively, by making novel predicted mutant proteins and
performing biochemical, biological, and structural studies. We will also validate our algorithms retrospectively,
using existing structures and data. All software will be released open-source.
项目总结。基于计算结构的蛋白质设计是一个令人兴奋的变革领域
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Bruce R. Donald其他文献
Discovery, characterization, and redesign of potent antimicrobial thanatin orthologs from emChinavia ubica/em and emMurgantia histrionica/em targeting emE. coli/em LptA
从 emChinavia ubica/em 和 emMurgantia histrionica/em 中发现、表征和重新设计针对 emE. coli/em LptA 的强效抗菌 thanatin 直系同源物
- DOI:
10.1016/j.yjsbx.2023.100091 - 发表时间:
2023-12-01 - 期刊:
- 影响因子:5.100
- 作者:
Kelly Huynh;Amanuel Kibrom;Bruce R. Donald;Pei Zhou - 通讯作者:
Pei Zhou
Resistor: an algorithm for predicting resistance mutations using Pareto optimization over multistate protein design and mutational signatures
Resistor:一种使用多态蛋白质设计和突变特征的帕累托优化来预测抗性突变的算法
- DOI:
- 发表时间:
2022 - 期刊:
- 影响因子:0
- 作者:
N. Guerin;A. Feichtner;Eduard Stefan;T. Kaserer;Bruce R. Donald - 通讯作者:
Bruce R. Donald
span style=color:#0070C0;font-family:quot;Calibriquot;,quot;sans-serifquot;;font-size:12pt;An Efficient Parallel Algorithm for Accelerating Computational Protein Design/span
一种加速计算蛋白质设计的高效并行算法
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:5.8
- 作者:
Yichao Zhou;Wei Xu;Bruce R. Donald;Jianyang Zen - 通讯作者:
Jianyang Zen
A theory of manipulation and control for microfabricated actuator arrays
微加工执行器阵列的操纵和控制理论
- DOI:
10.1109/memsys.1994.555606 - 发表时间:
1994 - 期刊:
- 影响因子:0
- 作者:
K. Bohringer;Bruce R. Donald;Robert Mihailovich;Noel C. MacDonald - 通讯作者:
Noel C. MacDonald
<span style="color:#0070C0;font-family:&quot;Calibri&quot;,&quot;sans-serif&quot;;font-size:12pt;">An Efficient Parallel Algorithm for Accelerating Computational Protein Design</span>
- DOI:
- 发表时间:
2014 - 期刊:
- 影响因子:5.8
- 作者:
Yichao Zhou;Wei Xu;Bruce R. Donald;Jianyang Zen; - 通讯作者:
Bruce R. Donald的其他文献
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{{ truncateString('Bruce R. Donald', 18)}}的其他基金
Diversity Supplement: Computational and Experimental Studies of Protein Structure and Design
多样性补充:蛋白质结构和设计的计算和实验研究
- 批准号:
10579649 - 财政年份:2022
- 资助金额:
$ 35.4万 - 项目类别:
Computational and Experimental Studies of Protein Structure and Design
蛋白质结构和设计的计算和实验研究
- 批准号:
10554322 - 财政年份:2022
- 资助金额:
$ 35.4万 - 项目类别:
Computational and Experimental Studies of Protein Structure and Design
蛋白质结构和设计的计算和实验研究
- 批准号:
10727023 - 财政年份:2022
- 资助金额:
$ 35.4万 - 项目类别:
Computational and Experimental Studies of Protein Structure and Design
蛋白质结构和设计的计算和实验研究
- 批准号:
10793426 - 财政年份:2022
- 资助金额:
$ 35.4万 - 项目类别:
Computational and Experimental Studies of Protein Structure and Design
蛋白质结构和设计的计算和实验研究
- 批准号:
10330495 - 财政年份:2022
- 资助金额:
$ 35.4万 - 项目类别:
Automated NMR Assignment and Protein Structure Determination
自动 NMR 分配和蛋白质结构测定
- 批准号:
7940504 - 财政年份:2009
- 资助金额:
$ 35.4万 - 项目类别:
Computational Active-Site Redesign and Binding Prediction via Molecular Ensembles
通过分子整体的计算活性位点重新设计和结合预测
- 批准号:
8025987 - 财政年份:2008
- 资助金额:
$ 35.4万 - 项目类别:
Computational Active-Site Redesign and Binding Prediction via Molecular Ensembles
通过分子整体的计算活性位点重新设计和结合预测
- 批准号:
7462701 - 财政年份:2008
- 资助金额:
$ 35.4万 - 项目类别:
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