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.

 

Thanks for your time!