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Predicting Binding Free Energies in a Large Combinatorial Chemical Space Using Multisite λ Dynamics

Jonah Z. Vilseck, Kira A. Armacost, Ryan L. Hayes, Garrett B. Goh, Charles L. Brooks
2018 Journal of Physical Chemistry Letters  
as potent as a tight binding reference compound (i.e., as potent as 56 nM).  ...  This is the largest exploration of chemical space using free energy methods known to date, requires only a few simulations, and identifies 55 new inhibitor designs against HIV-RT predicted to be at least  ...  A Pearson correlation of 0.968 and a mean unsigned error (MUE) of 0.52 kcal/mol are observed, suggesting that excellent agreement is achieved between the methods.  ... 
doi:10.1021/acs.jpclett.8b01284 pmid:29847134 pmcid:PMC6091208 fatcat:cuofiihkgneaxcskp6g6fu4h2y

Adaptive Landscape Flattening Accelerates Sampling of Alchemical Space in Multisite λ Dynamics

Ryan L. Hayes, Kira A. Armacost, Jonah Z. Vilseck, Charles L. Brooks
2017 Journal of Physical Chemistry B  
Multisite λ dynamics (MSλD) is a powerful emerging method in free energy calculation that allows prediction of relative free energies for a large set of compounds from very few simulations.  ...  Both scale with the size of the perturbed substituent and are removed by sharp biasing potentials and a new soft-core implementation, respectively.  ...  or a lack of sampling.  ... 
doi:10.1021/acs.jpcb.6b09656 pmid:28112940 pmcid:PMC5824625 fatcat:lhngiemf3vdyrlbuvwl4bfgyaa

Biasing Potential Replica Exchange Multi-Site λ-Dynamics for Efficient Free Energy Calculations of Protein-Ligand Interactions

Kira A. Armacost, Garrett B. Goh, Charles L. Brooks
2015 Biophysical Journal  
on a common framework with relative ease.  ...  The perturbations spanned by as much as 60 Å 3 and we were able to model these with a 2.4 kcal/mol average unsigned error.  ...  Platform: Protein-Small Molecule Interactions 1788-Plat Biasing Potential Replica Exchange Multi-Site l-Dynamics for Efficient Free Energy Calculations of Protein-Ligand Interactions Kira A.  ... 
doi:10.1016/j.bpj.2014.11.1951 fatcat:nnfln5yko5hkxflb2sd7ik6lhm

Parametrization of halogen bonds in the CHARMM general force field: Improved treatment of ligand–protein interactions

Ignacio Soteras Gutiérrez, Fang-Yu Lin, Kenno Vanommeslaeghe, Justin A. Lemkul, Kira A. Armacost, Charles L. Brooks, Alexander D. MacKerell
2016 Bioorganic & Medicinal Chemistry  
A halogen bond is a highly directional, non-covalent interaction between a halogen atom and another electronegative atom.  ...  A strategy to overcome this problem is to attach a positively charged virtual particle to the halogen.  ...  cutoff of 12 Å.  ... 
doi:10.1016/j.bmc.2016.06.034 pmid:27353885 pmcid:PMC5053860 fatcat:cvm4v2u5xncqpl7j2i7usvpabi

Structural understanding of non-nucleoside inhibition in an elongating herpesvirus polymerase

Robert P. Hayes, Mee Ra Heo, Mark Mason, John Reid, Christine Burlein, Kira A. Armacost, David M. Tellers, Izzat Raheem, Anthony W. Shaw, Edward Murray, Philip M. McKenna, Pravien Abeywickrema (+3 others)
2021 Nature Communications  
Here we report the ternary complex crystal structure of Herpes Simplex Virus 1 DNA polymerase bound to DNA and a 4-oxo-dihydroquinoline NNI, PNU-183792 (PNU), at 3.5 Å resolution.  ...  These results demonstrate that PNU inhibits replication by blocking association of dNTP and stalling the enzyme in a catalytically incompetent conformation, ultimately acting as a nucleotide competing  ...  Use of the IMCA-CAT beamline 17-ID at the Advanced Photon Source was supported by the companies of the Industrial Macromolecular Crystallography Association through a contract with Hauptman-Woodward Medical  ... 
doi:10.1038/s41467-021-23312-8 pmid:34031403 fatcat:zl5gdsldxvacppxrgampg43lqi

Molecular Mechanism for Isoform-Selective Inhibition of Acyl Protein Thioesterases 1 and 2 (APT1 and APT2)

Sang Joon Won, Dahvid Davda, Kristin J. Labby, Sin Ye Hwang, Rachel Pricer, Jaimeen D. Majmudar, Kira A. Armacost, Laura A. Rodriguez, Christina L. Rodriguez, Fei San Chong, Kristopher A. Torossian, Jasmine Palakurthi (+5 others)
2016 ACS Chemical Biology  
Herein we report the high-resolution structure of human APT2 in complex with ML349 (1.64 Å), as well as the complementary structure of human APT1 bound to ML348 (1.55 Å).  ...  Although the overall peptide backbone structures are nearly identical, each inhibitor adopts a distinct conformation within each active site.  ...  a c  ... 
doi:10.1021/acschembio.6b00720 pmid:27748579 pmcid:PMC5359770 fatcat:xmfewe35tbh23pziy5jwsz6lsu

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation

Chuan Hong, Noel J. Byrne, Beata Zamlynny, Srivanya Tummala, Li Xiao, Jennifer M. Shipman, Andrea T. Partridge, Christina Minnick, Michael J. Breslin, Michael T. Rudd, Shawn J. Stachel, Vanessa L. Rada (+10 others)
2021 Nature Communications  
AbstractNarcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles.  ...  Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition.  ...  extracellular region as a guide.  ... 
doi:10.1038/s41467-021-21087-6 pmid:33547286 fatcat:ggps73jvrbfx3my4vibiuehlqy

(Talk) Free Energy Methods in Drug Discovery: "It will be the most important field in computational chemistry" [article]

David Thompson, Kira Armacost, Eric C. Gladstone
2021 figshare.com  
collaborator, a researcher in the social sciences, to participate in this work [4, 5] and to help create : -Fairly worded questions -Balanced response metrics -A boundary between the act of data collection  ...  preprint of the manuscript, and this presentation https://figshare.com/projects/Free_Energy_Methods_in_Drug_Discovery/113688 Data Collection • A templated email including a link to the survey was  ...  A topical example [21] [21] https://yougov.co.uk/topics/health/survey-results/daily/2021/04/12/9d6aa/2 Where are we going?  ... 
doi:10.6084/m9.figshare.14798472.v1 fatcat:xxteaoxkwrf2tm4rv5egps4lku

Surface-Free Single-Molecule Force Spectroscopy

Yan Jiang, Wesley Wong
2015 Biophysical Journal  
on a common framework with relative ease.  ...  The perturbations spanned by as much as 60 Å 3 and we were able to model these with a 2.4 kcal/mol average unsigned error.  ...  Platform: Protein-Small Molecule Interactions 1788-Plat Biasing Potential Replica Exchange Multi-Site l-Dynamics for Efficient Free Energy Calculations of Protein-Ligand Interactions Kira A.  ... 
doi:10.1016/j.bpj.2014.11.1947 fatcat:a4kg5p3bozhepmma5n3brkugoe

Survey of Phosphorylation Near Drug Binding Sites in the Protein Data Bank (PDB) and their Effects

Kyle P. Smith, Kathleen M. Gifford, Joshua S. Waitzman, Sarah E. Rice
2015 Biophysical Journal  
on a common framework with relative ease.  ...  The perturbations spanned by as much as 60 Å 3 and we were able to model these with a 2.4 kcal/mol average unsigned error.  ...  Platform: Protein-Small Molecule Interactions 1788-Plat Biasing Potential Replica Exchange Multi-Site l-Dynamics for Efficient Free Energy Calculations of Protein-Ligand Interactions Kira A.  ... 
doi:10.1016/j.bpj.2014.11.1952 fatcat:rdwudwlagvezvbq267l4skk3n4

High-Speed Force Spectroscopy Unbinds Streptavidin-Biotin at the Velocity of Molecular Dynamics Simulations

Felix Rico, Andreas Russek, Helmut Grubmueller, Simon Scheuring
2015 Biophysical Journal  
on a common framework with relative ease.  ...  The perturbations spanned by as much as 60 Å 3 and we were able to model these with a 2.4 kcal/mol average unsigned error.  ...  Platform: Protein-Small Molecule Interactions 1788-Plat Biasing Potential Replica Exchange Multi-Site l-Dynamics for Efficient Free Energy Calculations of Protein-Ligand Interactions Kira A.  ... 
doi:10.1016/j.bpj.2014.11.1948 fatcat:5nf66wokivej5iovh552mthhju

The Princess and the Pea: A Story of Cell Mechanics

Mehdi Roeinpeikar, Qian Xu, Xuefeng Wang, Taekjip Ha
2015 Biophysical Journal  
on a common framework with relative ease.  ...  The perturbations spanned by as much as 60 Å 3 and we were able to model these with a 2.4 kcal/mol average unsigned error.  ...  Platform: Protein-Small Molecule Interactions 1788-Plat Biasing Potential Replica Exchange Multi-Site l-Dynamics for Efficient Free Energy Calculations of Protein-Ligand Interactions Kira A.  ... 
doi:10.1016/j.bpj.2014.11.1949 fatcat:vfwsxzv7vfbzdjdj3wplfdxpn4

Identification and Characterization of Protein-Protein Interaction Effectors Targeting the Invasion Machinery of the Malaria Parasite

Lauren E. Boucher, Christine S. Hopp, Photini Sinnis, Jürgen Bosch
2015 Biophysical Journal  
on a common framework with relative ease.  ...  The perturbations spanned by as much as 60 Å 3 and we were able to model these with a 2.4 kcal/mol average unsigned error.  ...  Armacost, Garrett B. Goh, Charles L. Brooks. Department of Chemistry, University of Michigan, Ann Arbor, MI, USA.  ... 
doi:10.1016/j.bpj.2014.11.1953 fatcat:3flcvyl4kzfjzlsnxwtiityglu

Free Energy Methods in Drug Discovery: "It will be the most important field in computational chemistry."

David Thompson, Kira Armacost, Eric C. Gladstone
2021 figshare.com  
The application of rigorous free energy methodologies to the field of drug discovery is a complex interplay between the description of the methodology in the form of a software (as provided by academic  ...  or commercial vendors), and the use of the software in the context of a biological target or an evolving drug discovery effort (as performed by both academic and industrial practitioners).  ...  Colorado) for providing a brief review of the inception and growth of the alchemistry.org community.  ... 
doi:10.6084/m9.figshare.14589444.v1 fatcat:qjtc3izc2fcvxcldpjl2yxrttm