Mapping Fitness and Free Energy Landscapes of Proteins
Mapping Fitness and Free Energy Landscapes of Proteins
批准号:
10609895
负责人:
Ronald Levy
金额:
$37.13万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-05-01 至 2024-04-30
关键词:
Amino Acid SequenceBase SequenceBindingBiochemicalBiologyBiophysicsCatalytic DomainCollaborationsColoradoComparative StudyComplexDataDrug resistanceFox Chase Cancer CenterFree EnergyGenesGoalsHIVHIV-1HumanIndividualKineticsLigandsMapsMethodsModelingMolecularMolecular ConformationMutationPatternPharmaceutical PreparationsPhosphotransferasesPlayPropertyProtein ConformationProtein FamilyProteinsRationalizationRegulationRoleSamplingSequence AlignmentStatistical MechanicsStructureThermodynamicsUniversitiesconformational conversiondesigndimerfitnessinhibitorinsightkinase inhibitormolecular dynamicsmolecular recognitionpressureresistance mutationsimulationsmall moleculestructural biologytheoriestool
中文摘要
项目摘要
我们的长期目标是整合基于统计力学的结构和序列方法
了解蛋白质分子识别的关键特征,以及蛋白质的适应性和功能。
一般来说。
1.蛋白质复杂构象和适合度图谱
构象动力学在分子识别和统计调控中起着重要的作用
力学提供了一个框架,以获得一个全面的理论结合自由能的配体,
蛋白质。我们的目标是使用基于分子动力学模拟的先进采样方法,
构建足够准确的构象自由能景观,以预测热力学和
动力学性质,但同样重要的是,产生定性的见解的分子机制,
结合和变构构象转变。强大的反向推理统计方法正在被
开发用于研究蛋白质序列共变异和蛋白质适合度之间的关系。该公司-
蛋白质家族的多重序列比对中包含的突变对的变异将用于
建立序列模式的Potts Hamilton模型,可用于预测适应度的变化
以及推断个体构象倾向的特征
proteins.
2.激酶选择性的结构基础和小分子调控
人类激酶组编码约518种激酶(PKs),其构成最大类基因之一。
激酶结构生物学的进展为理解激酶的许多方面提供了一个概念框架
生物学我们与福克斯蔡斯癌症中心和哥伦比亚大学的合作者一起,
生物物理模拟和进化序列为基础的方法,以合理化生化分析
激酶的研究,并设计一个框架,了解选择性的分子机制,
激酶抑制剂的作用。
3. HIV-1蛋白的抑制与耐药机制
我与科罗拉多大学、哈佛大学和斯克里普斯大学的研究小组合作,
HIV-1蛋白小分子抑制的基础,耐药性机制,以及
HIV蛋白质在不同HIV进化枝中适合度的比较研究。变构HIV-1 IN抑制剂称为
ALLINI是一类重要的新型抗HIV-1药物。ALLINI结合IN催化核心结构域(CCD)
二聚体界面占据LEDGF的主要结合口袋。利用构象自由能
模拟工具和基于序列的工具,我们正在开发,以了解相关的突变,我们是
与我们的合作者一起确定ALLINI的抑制机制,以及药物治疗的基础。
阻力
英文摘要
Project Summary
Our long term goal is to integrate structure and sequence based approaches founded in statistical mechanics
to understand key features of molecular recognition by proteins, as well as protein fitness and function more
generally.
1. Mapping Complex Conformational and Fitness Landscapes of Proteins
Conformational dynamics plays a fundamental role in the regulation of molecular recognition and statistical
mechanics provides the framework to derive a comprehensive theory for the binding free energy of a ligand to
a protein. Our goal is to use advanced sampling methods based on molecular dynamics simulations to
construct conformational free energy landscapes of sufficient accuracy to be predictive for thermodynamic and
kinetic properties, but also as important, to generate qualitative insights about the molecular mechanisms for
binding and allosteric conformational transitions. Powerful inverse inference statistical approaches are being
developed to study the relationship between protein sequence co-variation and protein fitness. The co-
variation of pairs of mutations contained in multiple sequence alignments of protein families will be used to
build Potts Hamiltonian models of the sequence patterns that can be used to predict the change in fitness
resulting from drug selection pressure, as well as infer features of the conformational propensities of individual
proteins.
2. The Structural Basis for Kinase Selectivity and Regulation by Small Molecules
The human kinome encodes about 518 kinases (PKs) which constitute one of the largest class of genes.
Progress in kinase structural biology offers a conceptual framework for understanding many aspects of kinase
biology. With our collaborators at the Fox Chase Cancer Center and Columbia University we are working on
biophysical simulation and evolutionary sequence based approaches to rationalize biochemical profiling
studies of kinases and to devise a framework for understanding the molecular mechanisms of selectivity of
kinase inhibitors to their targets.
3. Inhibition of HIV-1 Proteins and Mechanisms of Drug Resistance
In collaboration with groups at the University of Colorado, Harvard and Scripps, I am working on the allosteric
basis for inhibition by small molecules of HIV-1 proteins, on mechanisms of drug resistance, and on
comparative studies of the fitness of HIV proteins in different HIV clades. Allosteric HIV-1 IN inhibitors called
ALLINIs are an important new class of anti-HIV-1 agents. ALLINIs bind at the IN catalytic core domain (CCD)
dimer interface occupying the principal binding pocket of LEDGF. Using our conformational free energy
simulation tools and the sequence based tools we are developing to understand correlated mutations, we are
working with our collaborators to ascertain the inhibitory mechansims of ALLINIs, and the basis for drug
resistance.
期刊论文(2)
专著(0)
科研奖励(0)
会议论文
DOI:
10.7554/elife.83368
发表时间:
2022-12-23
期刊:
eLife
影响因子:
7.7
作者:
[Gizzio J, Thakur A, Haldane A, Levy RM]
通讯作者:
Levy RM
Mechanisms of HIV fitness and drug resistance inferred from high-resolution molecular dynamics and sequence co-variation models
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批准号:10750627
-
项目类别:
-
资助金额:$69.11万
-
财政年份:2023
-
负责人:Ronald Levy
-
依托单位:
Mapping Fitness and Free Energy Landscapes of Proteins
-
批准号:9906947
-
项目类别:
-
资助金额:$37.13万
-
财政年份:2019
-
负责人:Ronald Levy
-
依托单位:
Mapping Fitness and Free Energy Landscapes of Proteins
-
批准号:10577469
-
项目类别:
-
资助金额:$21.46万
-
财政年份:2019
-
负责人:Ronald Levy
-
依托单位:
Mapping Fitness and Free Energy Landscapes of Proteins
-
批准号:10402303
-
项目类别:
-
资助金额:$37.13万
-
财政年份:2019
-
负责人:Ronald Levy
-
依托单位:
Computer Cluster for Computational Biology and Biophysics
-
批准号:8826397
-
项目类别:
-
资助金额:$44.23万
-
财政年份:2015
-
负责人:Ronald Levy
-
依托单位:
Evolution of antiviral resistance mutations and their biological and biophysical implications
-
批准号:10242909
-
项目类别:
-
资助金额:$117.56万
-
财政年份:2012
-
负责人:Ronald Levy
-
依托单位:
Evolution of antiviral resistance mutations and their biological and biophysical implications
-
批准号:10363026
-
项目类别:
-
资助金额:$64.71万
-
财政年份:2012
-
负责人:Ronald Levy
-
依托单位:
Computer Simulations of Protein Structure and Dynamics
-
批准号:7932626
-
项目类别:
-
资助金额:$14.53万
-
财政年份:2009
-
负责人:Ronald Levy
-
依托单位:
ATLR 9 AGONIST, COMBINED WITH LOCAL RADIATION IN RECURRENT LOW-GRADE LYMPHOMAS
-
批准号:7605212
-
项目类别:
-
资助金额:$4.45万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
CLINICAL TRIAL: KLH WITH GM-CSF, IN PATIENTS WITH FOLLICULAR NON-HODGKIN'S LYMPH
-
批准号:7717852
-
项目类别:
-
资助金额:$0.05万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
CLINICAL TRIAL: ATLR 9 AGONIST, COMBINED WITH LOCAL RADIATION IN RECURRENT LOW-G
-
批准号:7717872
-
项目类别:
-
资助金额:$0.98万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
Computer Cluster for Computational and Structural Biology
-
批准号:7217100
-
项目类别:
-
资助金额:$29.09万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
KLH WITH GM-CSF, IN PATIENTS WITH FOLLICULAR NON-HODGKIN'S LYMPHOMA
-
批准号:7605175
-
项目类别:
-
资助金额:$0.64万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
VACCINE THERAPY FOR MULTIPLE MYELOMA ALLOGENEIC DENDRITIC CELLS
-
批准号:7605222
-
项目类别:
-
资助金额:$0.94万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
PATIENTS WITH STABLE OR PROGRESSIVE GRADE 1 OR 2 FOLLICULAR B-CELL LYMPHOMAS
-
批准号:7605251
-
项目类别:
-
资助金额:$0.35万
-
财政年份:2007
-
负责人:Ronald Levy
-
依托单位:
ATLR 9 AGONIST, COMBINED WITH LOCAL RADIATION IN RECURRENT LOW-GRADE LYMPHOMAS
-
批准号:7375281
-
项目类别:
-
资助金额:$0.53万
-
财政年份:2005
-
负责人:Ronald Levy
-
依托单位:
VACCINE THERAPY FOR MULTIPLE MYELOMA UTILIZING ALLOGENEIC DENDRITIC CELLS
-
批准号:7375297
-
项目类别:
-
资助金额:$0.22万
-
财政年份:2005
-
负责人:Ronald Levy
-
依托单位:
PROTOCOL G2002-09: A PHASE II STUDY TO EVALUATE THE SAFETY AND EFFICACY
-
批准号:7375226
-
项目类别:
-
资助金额:$1.25万
-
财政年份:2005
-
负责人:Ronald Levy
-
依托单位:
IMMUNOTHERAPY IN PATIENTS WITH FOLLICULAR NON-HODGKIN'S LYMPHOMA
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批准号:7375218
-
项目类别:
-
资助金额:$2.05万
-
财政年份:2005
-
负责人:Ronald Levy
-
依托单位:
Training for Integrative Proteomics Technologies(RMI)
-
批准号:7271214
-
项目类别:
-
资助金额:$12.11万
-
财政年份:2004
-
负责人:Ronald Levy
-
依托单位:
海外基金