Statistical design and analysis of binding affinity experiments
Thesis committee meeting
Bas Rustenburg
Applications to protonation state effects in kinase inhibition
Introduction
Subjects that I aim to become expert in by the end of my project
Bayesian models of experiments
Uncertainty estimation, model selection and experimental design using statistics.
Protonation state effects in kinases
Neeb et al. J. Med. Chem., 2014, 57 (13), pp 5554–5565
Where do they matter, and how can we exploit these?
Making sophisticated statistical tools accessible to non-programmers and non-statisticians
"Writing code that no one can run is a waste of time."
IMPORTANT DATES
Jun 2013 –MSc degree at VU Amsterdam
Sep 2013 – started the PBSB program
Jun 2014 – Joined the Chodera lab
May 2015 – Passed ACE exam
Summer 2015 – Internship at Genentech
Jun 2016 – First committee meeting
Feb 2017 – Second committee meeting?
Fall 2017 – Third committee meeting?
Fall 2018 – Graduate?
Project Timeline
Planned publications
1. Constant-pH simulations of ligands in openmm, automated calibration routine for aminoacids and ligands using stochastic approximation technique
Showcase of our new code and its features
Goal : Submitted by Nov 2016
Planned publications
2. Bayesian hierarchical model of two-component and competitive-binding interaction in isothermal titration calorimetry experiments
Performing experiments, and showcase utility in experimental design.
Goal : Submitted by Feb 2017
Planned publications
3. Joint inference on pH dependent experiments, such as fluorescence at multiple pH’s and/or ITC with multiple buffers
(Co-)first author
Goal : Submitted by May 2017
Planned publications
4. Demonstrating Bayesian ITC in a comparative review of ITC experiments in literature
Reanalyzing public data using Bayesian ITC, developing new models when necessary to describe interesting side cases, such as multiple ligand binding etc.
Goal : Submitted by Aug 2017
Planned publications
5. Strategies for binding affinity inference from multiple types of data
- fluorescence, ITC, and free energy calculations
- Perform experimental design + risk/cost analysis
Goal : Submitted by Mar 2018
Planned publications
6. Exploiting protonation state effects in kinase inhibitor binding
Free energy calculations, validated by Bayesian ITC, and Bayesian fluorescence experiments.
Goal : Submitted by Apr 2018
Planned publications
7. Statistical software paper about tool that combines binding models from several sources
- User interface to make the work accessible, so that there is no need to learn how to program to use these methods
Goal : Submitted by Jul 2018
Career Objectives
On the short term,
- Pursue a postdoctoral research position that using the methods I develop during my PhD to obtain several high impact application papers.
Career Objectives
On the long term
- Faculty member in a Dutch university, applying statistics to analytical (bio)chemistry, or potentially another type of applied statistics,
- Potentially interested in an east coast US position, depending on city and university, personal life situation at that time.
Career Objectives
Alternative careers
- Scientific software development
- preferably not molecular dynamics
- Biotech company, potentially a startup
- Likely not pharma company, though I would consider it if other options scarce
Past publications
2016:
Measuring experimental cyclohexane-water distribution coefficients for the SAMPL5 challenge.
Rustenburg, Arien S.; Dancer, Justin; Lin, Baiwei; Feng, Jianwen; Ortwine, Daniel F.; Mobley, David L.; Chodera, John D.: Submitting to Journal of computer-aided molecular design this week.
Past publications
2016:
Polarize or Not to Polarize? Charge-on-Spring versus KBFF Models for Water and Methanol Bulk and Vapor-Liquid Interfacial Mixtures.
Ploetz, Elizabeth A.; Rustenburg, Arien S.; Geerke, Daan P.; Smith, Paul E. (2016): To In Journal of chemical theory and computation 12 (5), pp. 2373–2387. DOI: 10.1021/acs.jctc.5b01115.
Past publications
2015:
Toward Automated Benchmarking of Atomistic Force Fields: Neat Liquid Densities and Static Dielectric Constants from the ThermoML Data Archive.
Beauchamp, Kyle A.; Behr, Julie M.; Rustenburg, Arien S.; Bayly, Christopher I.; Kroenlein, Kenneth; Chodera, John D. (2015)
In The journal of physical chemistry. B 119 (40), pp. 12912–12920
Past publications
2015:
Hypoxia Induces Production of L-2-Hydroxyglutarate.
Intlekofer, Andrew M.; Dematteo, Raymond G.; Venneti, Sriram; Finley, Lydia W. S.; Lu, Chao; Judkins, Alexander R. et al. (2015):In Cell metabolism 22 (2), pp. 304–311. DOI: 10.1016/j.cmet.2015.06.023.
Past publications
2012:
QM/MM-Based Fitting of Atomic Polarizabilities for Use in Condensed-Phase Biomolecular Simulation
Vosmeer, C. Ruben; Rustenburg, Arien S.; Rice, Julia E.; Horn, Hans W.; Swope, William C.; Geerke, Daan P. (2012):
In Journal of chemical theory and computation 8 (10), pp. 3839–3853.