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Markov State Model approaches for folding, binding and design

Award Number: R01GM123296
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Markov State Model approaches for folding, binding and design - Project Summary Understanding the conformational dynamics of proteins and their binding partners is crucial to predicting and designing their function. Molecular simulations are suitable for this task, but remain challenging for ligand binding systems where dissociation occurs on very slow time scales. We are developing new Markov state model (MSM) approaches, which describe conformational dynamics as a network of transitions between metastable states, to address this challenge. Multi-scale Markov models (MEMMs) offer a robust framework for building variationally optimal models of dynamics on long time scales, from ensembles of short trajectories sampled in biased thermodynamic ensembles, to predict ligand binding affinities, rates and mechanisms. During the coronavirus pandemic, our group used the distributed computing platform Folding@home (FAH) to perform virtual screening of SARS-CoV-2 main protease inhibitors by utilizing expanded-ensemble (EE) simulations, in which multiple alchemical intermediates can be sampled in a single simulation, to estimate binding free energies. This has inspired us to combine EE and MSM methods that can leverage the power of FAH to make fundamental advances in virtual screening and molecular design, in three specific aims: Our first aim is to improve EE methods for computing ligand binding free energies. In collaboration with the Shirts Lab, we seek to understand and ameliorate convergence issues, and explore and unify related approaches. We will investigate how well EE estimates of free energies of mutations can be used with MEMMs to predict changes in protein folding stability and rates. Finally, we will work with the Karanicolas Lab to determine the extent to which EE-calculated ABFEs on FAH can be used alongside advanced machine learning classifiers to discover both active and potent inhibitors from structure-based virtual screening studies. Our second aim is to develop a combined metadynamics (metaD) + MEMM approach for modeling binding reactions. We will develop and test two different strategies in which metaD is used to derive negative potentials of mean force along binding reaction coordinates that can be used as bias potentials for constructing multi- ensemble Markov models (MEMMs) of ligand binding. We will test these methods in toy binding systems, and small ligands of L99A lysozyme. Finally, we will apply metaD+MEMMs to predict affinities, rates and mechanisms of the macrolide natural product carolacton binding to FolD and its known drug-resistant mutants. Our third aim is to examine the extent to which solution-state preorganization determines binding affinity, and whether simulation-based modeling can use this idea quantitatively for computational design. For a corpus of 105 cyclic peptides with published affinities, EE+MSM approaches will test the validity of a two-step conformational selection model. The results of this work will guide the design, testing and optimization of cyclic peptide binders to disrupt dimerization of the tumor suppressor PTEN, a collaboration with the Rongsheng Wang Lab at Temple, to find new diagnostics/therapeutics for cancer metastasis.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $368,343 )
2024	2024	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1805 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	000	8	7/30/2024	NON-COMPETING CONTINUATION	$368,343
														Subtotal = $368,343

Issue Date FY: 2023 ( Subtotal = $368,343 )
2023	2023	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	001	7	6/13/2023	NON-COMPETING CONTINUATION	$368,343
2023	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	5/15/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $368,343

Issue Date FY: 2022 ( Subtotal = $397,593 )
2022	2022	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	000	6	9/21/2022	COMPETING CONTINUATION	$397,593
														Subtotal = $397,593

Issue Date FY: 2021 ( Subtotal = $295,617 )
2021	2021	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	000	5	5/3/2021	NON-COMPETING CONTINUATION	$295,617
														Subtotal = $295,617

Issue Date FY: 2020 ( Subtotal = $395,331 )
2020	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	4/16/2020	NON-COMPETING CONTINUATION	$295,617
2020	2020	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	001	4	7/2/2020	SUPPLEMENT FOR EXPANSION	$99,714
														Subtotal = $395,331

Issue Date FY: 2019 ( Subtotal = $295,617 )
2019	2019	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	4/30/2019	NON-COMPETING CONTINUATION	$295,617
														Subtotal = $295,617

Issue Date FY: 2018 ( Subtotal = $295,617 )
2018	2018	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	5/18/2018	NON-COMPETING CONTINUATION	$29,562
2018	2018	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	3/29/2018	NON-COMPETING CONTINUATION	$266,055
														Subtotal = $295,617

Issue Date FY: 2017 ( Subtotal = $295,617 )
2017	2017	TEMPLE UNIVERSITY-OF THE COMMONWEALTH SYSTEM OF HIGHER EDUCATION	1801 N BROAD ST	PHILADELPHIA	PA	19122	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	4/11/2017	NEW	$295,617
														Subtotal = $295,617

Grand Total All Awards = $2,712,078

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Markov State Model approaches for folding, binding and design

Award Number: R01GM123296

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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