A novel small-molecule pan-Id antagonist inhibits pathologic ocular neovascularization

agx51.png

Paulina M. Wojnarowicz, Raquel Lima e Silva, Masayuki Ohanka, Sang Bae Lee, Yvette Chin, Anita Kulukian, Sung-Hee Chang, Bina Desai, Marta Garcia Escolano, Riddhi Shah, Marta Garcia-Cao, Sijia Xu, Rashmi Thakar, Yehuda Goldgur, Meredith A. Miller, Ouathek Ouerfelli, Guangli Yang, Tsutomu Arakawa, Steven K. Albanese, William A. Garland, Glenn Stoller, Jaideep Chaudhary, Rajesh Soni, John Philip, Ronald C. Hendrickson, Antonio Iavarone, Andrew J. Dannenberg, John D. Chodera, Nikola Pavletich, Anna Lasorella, Peter A. Campochiaro, and Robert Benezra
Submitted.

We report the discovery and characterization of a small molecule, AGX51, with the surprising ability to inhibit the interaction of Id1 with E47, which leads to ubiquitin-mediated degradation of Ids.

The dynamic conformational landscapes of the protein methyltransferase SETD8

SETD8-landscape.png

Rafal P. Wiewiora*, Shi Chen*, Fanwang Meng, Nicolas Babault, Anqi Ma, Wenyu Yu, Kun Qian, Hao Hu, Hua Zou, Junyi Wang, Shijie Fan, Gil Blum, Fabio Pittella-Silva, Kyle A. Beauchamp, Wolfram Tempel, Hualing Jiang, Kaixian Chen, Robert Skene, Y. George Zheng, Peter J. Brown, Jian Jin, John D. Chodera+, and Minkui Luo+.
Submitted. [bioRxiv] 
* These authors contributed equally to this work
+ Co-corresponding authors

In this work, we show how targeted X-ray crystallography using covalent inhibitors and depletion of native ligands to reveal structures of low-population hidden conformations can be combined with massively distributed molecular simulation to resolve the functional dynamic landscape of the protein methyltransferase SETD8 in unprecedented atomistic detail. Using an aggregate of six milliseconds of fully atomistic simulation from Folding@home, we use Markov state models to illuminate the conformational dynamics of this important epigenetic protein.

Toward learned chemical perception of force field typing rules

Camila Zanette Caitlin C. Bannan Christopher I. Bayly Josh Fass Michael K. Gilson Michael R. Shirts John Chodera David L. Mobley
Submitted. [ChemRxiv] [GitHub]

We show how machine learning can learn typing rules for molecular mechanics force fields within a Bayesian statistical framework.

Overview of the SAMPL6 host-guest binding affinity prediction challenge

Andrea RizziSteven MurkliJohn N. McNeillWei YaoMatthew SullivanMichael K. Gilson, Michael W. Chiu, Lyle IsaacsBruce C. GibbDavid L. Mobley*, John D. Chodera*
* denotes co-corresponding authors
Journal of Computer-Aided Molecular Design special issue on SAMPL6, just accepted
[bioRxiv] [GitHub]

We present an overview of the host-guest systems and participant performance for the SAMPL6 host-guest blind affinity prediction challenges, assessing how well various physical modeling approaches were able to predict ligand binding affinities for simple ligand recognition problems where receptor sampling and protonation state effects are eliminated due to the simplicity of supramolecular hosts. We find that progress is now stagnated likely due to force field limitations.

An open library of human kinase domain constructs for automated bacterial expression

kinome-expression-tree.jpg

Steven K. Albanese*, Daniel L. Parton*, Mehtap Isik**, Lucelenie Rodríguez-Laureano**, Sonya M. Hanson,  Julie M. Behr, Scott Gradia, Chris Jeans, Nicholas M. Levinson, Markus A. Seeliger, and John D. Chodera.
* co-first author; ** co-second author
Biochemistry 57:4675, 2018. [DOI] [bioRxiv]
Interactive data browser: [github.io]
Plasmids available via AddGene

Human kinase catalytic domains---the therapeutic target of selective kinase inhibitors used in the treatment of cancer and other diseases---are notoriously difficult and expensive to express in insect or human cells. Here, we utilize the phosphatase co-expression technology developed by Markus Seeliger (now at Stony Brook) to develop a library of human kinase catalytic domains for facile and inexpensive expression in bacteria.

pKa measurements for the SAMPL6 prediction challenge for a set of kinase inhibitor-like fragments

Mehtap Işık, Dorothy Levorse, Ariën S. Rustenburg, Ikenna E. Ndukwe, Heather Wang , Xiao Wang , Mikhail Reibarkh , Gary E. Martin , Alexey A. Makarov , David L. Mobley, Timothy Rhodes*, John D. Chodera*.
* co-corresponding authors
Journal of Computer-Aided Molecular Design special issue on SAMPL6, just accepted.
[bioRxiv] [Supplementary Tables and Figures] [Supplementary Data (includes Sirius T3 reports on all measurements)]

The SAMPL5 blind challenge exercises identified neglect of protonation state effects as a major accuracy-limiting factor in physical modeling of biomolecular interactions. In this study, we report the experimental measurements behind a SAMPL6 blind challenges in which we assess the ability of community codes to predict small molecule pKas for small molecule resembling fragments of selective kinase inhibitors.

OpenPathSampling: A Python framework for path sampling simulations. II. Building and customizing path ensembles and sample schemes

David W.H. Swenson, Jan-Hendrik Prinz, Frank Noé, John D. Chodera, Peter G. Bolhuis
Journal of Chemical Theory and Computation, just accepted. [bioRxiv] [GitHub] [openpathsampling.org]

To make powerful path sampling techniques broadly accessible and efficient, we have produced a new Python framework for easily implementing path sampling strategies (such as transition path and interface sampling) in Python. This second publication describes advanced aspects of the theory and details of how to customize path ensembles.

OpenPathSampling: A Python framework for path sampling simulations. I. Basics

David W.H. Swenson, Jan-Hendrik Prinz, Frank Noé, John D. Chodera, Peter G. Bolhuis
Journal of Chemical Theory and Computation, just accepted. [bioRxiv] [GitHub] [openpathsampling.org]

To make powerful path sampling techniques broadly accessible and efficient, we have produced a new Python framework for easily implementing path sampling strategies (such as transition path and interface sampling) in Python. This first publication describes some of the theory and capabilities behind the approach.

Predicting resistance of clinical Abl mutations to targeted kinase inhibitors using alchemical free-energy calculations

Kevin Hauser, Christopher Negron, Steven K. Albanese, Soumya Ray, Thomas Steinbrecher, Robert Abel, John D. Chodera, and Lingle Wang.
Communications Biology 1:70, 2018 [DOI] [input files and analysis scripts]

In our first collaborative paper with Schrödinger, we present the first comprehensive benchmark assessing the ability for alchemical free energy calculations to predict clinical mutational resistance or susceptibility to targeted kinase inhibitors using the well-studied kinase Abl, the target of therapy for chronic myelogenous leukemia (CML).

Bayesian analysis of isothermal titration calorimetry for binding thermodynamics

Trung Hai Nguyen, Arien S. Rustenburg, Stefan G. Krimmer, Hexi Zhang, John D. Clark, Paul A. Novick, Kim Branson, Vijay S. Pande, John D Chodera, David D. L. Minh.
PLoS One, in press. [bioRxiv]

We show how Bayesian inference can produce greatly improved estimates of statistical uncertainty from isothermal titration calorimetry (ITC) experiments, allowing the joint distribution of thermodynamic parameter uncertainties to be inferred.

Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia

Gerard Minuesa, Steven K Albanese, Arthur Chow, Alexandra Schurer, Sun-Mi Park, Christina Z. Rotsides, James Taggart, Andrea Rizzi, Levi N. Naden, Timothy Chou, Saroj Gourkanti, Daniel Cappel, Maria C Passarelli, Lauren Fairchild, Carolina Adura, Fraser J Glickman, Jessica Schulman, Christopher Famulare, Minal Patel, Joseph K Eibl, Gregory M Ross, Derek S Tan, Christina S Leslie, Thijs Beuming, Yehuda Goldgur, John D Chodera, Michael G Kharas
Preprint: [bioRxiv]

We use absolute alchemical free energy calculations to identify the likely interaction site for a small hydrophobic ligand that shows activity against MUSASHI in AML.

Quantifying configuration-sampling error in Langevin simulations of complex molecular systems

quantifying-langevin-error.jpg

Josh Fass, David Sivak , Gavin E. Crooks, Kyle A. Beauchamp, Benedict Leimkuhler, and John Chodera.
Entropy 20:318, 2018. [DOI] [GitHub] [bioRxiv preprint]

Molecular dynamics simulations necessarily use a finite timestep, which introduces error or bias in the sampled configuration space density that grows rapidly with increasing timestep. For the first time, we show how to compute a natural measure of this error---the KL divergence---in both phase and configuration space for a widely used family of Langevin integrators, and show that VRORV is generally superior for simulation of molecular systems.

Open Force Field Consortium: Escaping atom types using direct chemical perception with SMIRNOFF v0.1

David Mobley, Caitlin C. Bannan, Andrea Rizzi, Christopher I. Bayly, John D. Chodera, Victoria T Lim, Nathan M. Lim, Kyle A. Beauchamp, Michael R. Shirts, Michael K. Gilson, Peter K. Eastman.
Preprint ahead of submission: [DOI]

We describe the philosophy behind a modern approach to molecular mechanics forcefield parameterization, and present initial results for the first SMIRNOFF-encoded forcefield: SMIRNOFF99Frosst.

A dynamic mechanism for allosteric activation of Aurora kinase A by activation loop phosphorylation

Emily F. Ruff, Joseph M. Muretta, Andrew Thompson, Eric W. Lake, Soreen Cyphers, Steven K. Albanese, Sonya M. Hanson, Julie M. Behr, David D. Thomas,  John D. Chodera, and Nicholas M. Levinson. 
eLife 7:e32766, 2018. [DOI] [bioRxiv]

We show that, contrary to the canonical belief that activation shifts DFG-out to DFG-in populations, phosphorylation of AurA does not shift DFG-in/out equilibrium but instead remodels the conformational distribution of the DFG-in state.

Biomolecular simulations under realistic macroscopic salt conditions

Gregory A. Ross, Ariën S. Rustenburg, Patrick B. Grinaway, Josh Fass, and John D. Chodera
Journal of Physical Chemistry B 122:5466, 2018. [DOI] [bioRxiv] [simulation code] [results and analysis scripts]

We show how NCMC can be used to implement an efficient osmostat in molecular dynamics simulations to model realistic fluctuations in ion environments around biomolecules, and illustrate how the local salt environment around biological macromolecules can differ substantially from bulk.

Binding Modes of Ligands Using Enhanced Sampling (BLUES): Rapid Decorrelation of Ligand Binding Modes Using Nonequilibrium Candidate Monte Carlo

Samuel Gill, Nathan M. Lim, Patrick Grinaway, Ariën S. Rustenburg, Josh Fass, Gregory Ross, John D. Chodera, and David Mobley.
Journal of Physical Chemistry B 22:5579, 2018. [DOI] [ChemRxiv] [GitHub]

Nonequilibrium candidate Monte Carlo can be used to accelerate the sampling of ligand binding modes by orders of magnitude over instantaneous Monte Carlo.

OpenMM 7: Rapid Development of High Performance Algorithms for Molecular Dynamics

Peter Eastman, Jason Swails, John D. Chodera, Robert T. McGibbon, Yutong Zhao, Kyle A. Beauchamp, Lee-Ping Wang, Andrew C. Simmonett, Matthew P. Harrigan, Chaya D. Stern, Rafal P. Wiewiora, Bernard R. Brooks, Vijay S. Pande. PLoS Computational Biology 13:e1005659, 2017. [DOI] [bioRxiv] [website] [GitHub]

We describe the latest version of OpenMM, a GPU-accelerated framework for high performance molecular simulation applications.

Approaches for calculating solvation free energies and enthalpies demonstrated with an update of the FreeSolv database

Guilherme Duarte Ramos MatosDaisy Y. KyuHannes H. LoefflerJohn D. ChoderaMichael R. ShirtsDavid Mobley
Journal of Chemical Engineering Data, Journal of Chemical Engineering Data 62:1559, 2017. [DOI] [bioRxiv] [GitHub]

We review alchemical methods for computing solvation free energies and present an update (version 0.5) to the FreeSolv database of experimental and calculated hydration free energies of neutral compounds.

Ensembler: Enabling high-throughput molecular simulations at the superfamily scale

Daniel L. Parton, Patrick B. Grinaway, Sonya M. Hanson, Kyle A. Beauchamp, and John D. Chodera
PLoS Computational Biology 12:e1004728, 2016. [DOI] [PDF] [bioRxiv] / data: [Dryad] / code: [GitHub]

We demonstrate a new tool that enables---for the first time---massively parallel molecular simulation studies of biomolecular dynamics at the superfamily scale, illustrating its application to protein tyrosine kinases, an important class of drug targets in cancer.

A simple method for automated equilibration detection in molecular simulations

John D. Chodera.
J. Chem. Theor. Comput. 12:1799, 2016. [DOI[PDF] / code to reproduce manuscript: [GitHub] / preprint: [bioRxiv] / available in pymbar.timeseries

We present a simple scheme for automatically selecting how much initial simulation data to discard to equilibration or burn-in based on maximizing the number of statistically uncorrelated samples in the dataset.

Keywords: molecular simulation; molecular dynamics; burn-in; equilibration; production; analysis