2018 Workshop on Free Energy Methods, Kinetics and Markov State Models in Drug Design

Introduction

This first three days of the this workshop focus on free energy techniques—the latest innovations and use cases, force field parameterization as it touches these techniques, and sampling practices, among other things. The last two days focus on the study of the kinetics of biomolecular processes at the atomistic and systems scales, via in-silico approaches such as Markov State Models and other suitable techniques.

We as organizers believe that these techniques are even closer than before to making an impact in appropriate drug discovery applications, by allowing physics-based prediction of physical properties such as binding affinity, selectivity, solubility, and membrane permeability. However, a number of challenges still remain. This workshop provides a unique opportunity to assess where we are today and what challenges must be tackled next to bring the potential of free energy techniques to bear on real-world applications. We also seek to identify particular problems in drug discovery where these methods can have an impact.

Our goal in this workshop is to bring together experts from pharma and supporting industries, as well as academia, in an intense and focused workshop to identify challenges and help chart the path forward. We are particularly interested in hearing about use cases, pitfalls and their solutions, and so on. We also firmly believe we can learn a great deal from failure, so we hope participants will go beyond just highlighting success stories to provide more detailed insight into successes and failures.

Dates and Locations

The meeting runs Monday, May 14th to Friday, May 18th, 2018.

Monday Night, May 14th

A reception will be held on Monday night at Silicon Therapeutics HQ, 70 Fargo Street, Ste 205, Boston, MA 02210

Tuesday, May 15th to Friday, May 18th

The remainder of the meeting will be hosted at The Novartis Institutes for Biomedical Research, Auditorium, 250 Massachusetts Ave, Cambridge, MA, 02139

On street metered parking is usually limited to two hours. There are public lots around the area. You can check public parking location and rates at http://en.parkopedia.com/parking/cambridge.
If you're coming via public transportation, take the subway red line to Kendall Square.

Registration

4/5/18 Update: Registration for the meeting is now closed, except for speakers and meeting sponsors, due to capacity limits. Please contact Mike Schnieders (michael-schnieders@uiowa.edu) or another meeting organizer if you missed the registration window and would like consideration.

Workshop Themes

As in our previous workshop, participants should feel free to discuss work that highlights problems or limitations, present ideas on how these limitations may be overcome, and discuss new developments that are underway.

• Applications of Free Energy Methods in Drug Discovery
  • Multiple Examples of Lead Optimization for Different Biomolecular Targets
  • New Commercial Simulation Algorithms
• Free Energy Simulations: What Didn't Work and Why
  • Sampling and Convergence
  • Force Field Functional Form (i.e. to polarize or not to polarize) and Parameterization Quality
  • (Bio)chemical Effects: Protonation States, Tautomers, Salt Effects, Biological Unit, etc.
  • Simulation Set-up and Parameter Sensitivity
• Extending the domain of applicability of free energy calculations
  • Handling metals (would double the number of systems we can apply free energy calculations to)
  • Dealing with chemical effects (constant-pH, tautomers, counterions)
  • Force field parameterization for more exotic chemistries
  • Multiple binding sites / weak binders
• ADME-Tox and Physical Property Prediction
  • Solubilities, Membrane Permeability and Partition coefficients
  • HSA binding, hERG inhibition
  • Cytochromes P450 Metabolism
• Kinetics and Markov State Modeling
  • Optimization of Binding Kinetics
  • Handling Large Conformational Changes
  • New MSM Methodology for Drug Design
  • Discovery of Allosteric Binding Sites

Sponsors, Social Media and Streaming

Sponsors

We would like to thank the following sponsors:

Social Media

Twitter hashtags: #drugalchemy #drugmsm; add #discuss if you have a discussion topic suggestion
Slack: https://alchemistry.slack.com

Live Streaming

The conference this year reached capacity with a long waitlist. We will be trying to record the talks for later upload to YouTube to ensure everyone who wanted to attend still be a part of the community. We are also experimenting with capturing the slides directly and possibly streaming the talks so people can watch remotely in real time to be as engaging as possible.

If you would like to be notified when the stream goes live and when the videos are upload, be sure to sign up! (your e-mail will be kept private)

Monday night was streamed to YouTube and the remaining talks are individually recorded and uploaded. Links to each talk are attached to the schedule below for the individual speakers.

Schedule

The schedule of talks is shown below, including scheduled time for discussion.

Monday Night, May 14th

As a reminder, the venue for Monday night is Silicon Therapeutics HQ, 70 Fargo Street, Ste 205, Boston, MA 02210

Monday Night Stream

• 6:00-7:00 Welcome with Food and Drinks
• 7:00-7:15 Darrin York, Rutgers University: "Toward a GPU-Accelerated Free Energy Pipeline for High-throughput Lead Optimization"
• 7:15-7:30 Stefan Doerr, Acellera: "ACEMD-ai: Ab-initio machine learning calculations of small molecules quantum energies and forces"
• 7:30-7:45 Sergio Decherchi, BiKi Technologies: "Kinetics of Protein-Ligand Unbinding Via Smoothed Potential Molecular Dynamics Simulations"
• 7:45-9:00 Reception with Drinks

Tuesday, May 15th

As a reminder, the venue for Tues. - Fri. is The Novartis Institutes for Biomedical Research, Auditorium, 250 Massachusetts Ave, Cambridge, MA, 02139.

Free Energy Simulations in the Real World moderated by Woody Sherman

• 8:30-9:00 Coffee and pastries
• 9:00-9:10 Welcome and Opening Remarks by Mike Schnieders
• 9:10-9:40 Keynote by Mark Murcko (Listen to the talk)
• 9:40-10:10 Christina Schindler, Merck: "Large scale free energy calculations in drug discovery at Merck KGaA, Darmstadt, Germany" (Watch the talk)
• 10:10-10:30 Coffee break
• 10:30-11:00 Guanglei Cui, GSK: "Assessing the Performance of Relative Affinity Predictions: from Null Model to Null Systems" (Requested not to be recorded)
• 11:00-11:30 Aysegyl Ozen, Pfizer: "Lessons from retrospective FEP on NAMPT." (Watch the talk)
• 11:30-12:00 Katharina Meier, Bayer: "Binding Free Energy Calculations in Active Drug Discovery Projects." (Requested not to be recorded)
• 12:00-1:30 Lunch at Novartis with a moderated discussion.

Increasing the Domain of Applicability of Free Energy Simulations: Salt, pH, Force Fields and Proteins moderated by Jay Ponder

• 1:30-1:45 Greg Ross, Schrödinger: "Biomolecular simulations under realistic macroscopic salt conditions." (Watch the Talk)
• 1:45-2:00 Marie Laury, Washington U. in St. Louis: "Calculating host-guest binding free energies via the AMOEBA polarizable force field." (Watch the talk)
• 2:00-2:30 Jana Shen, U. of Maryland: "How to incorporate pH in protein-ligand binding free energy calculations." (Watch the talk)
• 2:30-3:00 Christopher Bayly, OpenEye Scientific Software: “SMIRNOFF and the Open Force Field Consortium.” (Watch the talk)
• 3:00-3:15 Coffee break
• 3:15-3:45 Matteo Aldeghi, Max Plank: "Predictions of ligand binding affinity changes upon protein mutation using non-equilibrium free energy calculations." (Requested not to be recorded)
• 3:45-4:15 Charlie Brooks, U. of Michigan: "Probing Epistasis in Protein Design with High-Throughput Free Energy Methods." (Watch the talk)
• 4:15-4:30 Coffee break
• 4:30-5:00 Pratyush Tiwary, U. of Maryland: "Designing dynamical maps for biomolecules with statistical mechanics & predictive artificial intelligence." (Watch the talk)
• 5:00-5:30 Thomas Simonson, Ecole Polytechnique: "Accurate PDZ:peptide binding free energies with additive and polarizable free energy simulations." (Watch the talk)
• 5:30-7:00 Poster Session

Wednesday, May 16th

Beyond Binding Affinity: Simulations for Membrane Permeability, Polymorphs, Hydration and Pose Prediction moderated by John Chodera

• 8:30-9:00 Coffee and pastries
• 9:00-9:30 Chris Chipot, U. of Illinois: "Influence of the membrane composition on its permeability to drugs." (Watch the talk)
• 9:30-10:00 Michael Shirts, U. of Colorado: "Free energies of crystal polymorphs: what sorts of approximations can we get away with?" (Watch the talk)
• 10:00-10:30 Dave Huggins, Tri-Institutional Therapeutics Discovery Institute: "Estimating Atomic Contributions to Small-Molecule Hydration and Protein-Ligand Binding Using Free-Energy Perturbation." (Watch the talk)
• 10:30-10:50 Coffee break
• 10:50-11:20 Lucie Delemotte, KTH Teoretisk fysik: "GMM with cross-validation allows a robust estimation of free energies: application to the Calmodulin conformational ensemble." (Watch the talk)
• 11:20-11:50 Germano Heinzelmann, U. Federal de Santa Catarina: "APRprotein: Attach-pull-release calculations applied to bromodomains as a pose refinement and ligand ranking tool." (Watch the talk)
• 11:50-1:20 Lunch at Novartis and moderated discussion.

Advances in Theory and Software for Free Energy Simulations moderated by Mike Schnieders

• 1:20-1:50 Sathesh Bhat, Schrödinger: "Solving Real World Drug Discovery Problems with Free Energy Calculations." (Requested not to be recorded)
• 1:50-2:20 Jean-Philip Piquemal, UPMC: "Accelerating free energy evaluation with Tinker-HP." (Watch the talk)
• 2:20-2:50 Woody Sherman, Silicon Therapeutics: "Overcoming Discovery Bottlenecks on Challenging Targets using Molecular Simulations in an Integrated Biology/Chemistry/Physics Company." (Requested not to be recorded)
• 2:50-3:10 Coffee break
• 3:10-3:40 Léa El Khoury, UC Irvine: "Absolute Binding Free Energy Predictions for Heat Shock Protein 90 (HSP90) Complexes." (Watch the talk)
• 3:40-4:10 Israel Cabeza de Vaca, Yale: "Estimating absolute binding free energies through Monte Carlo simulations." (Watch the talk)
• 4:10-4:30 Coffee break
• 4:30-5:00 David Ryan Koes, U. of Pittsburgh: "Docking Deeply: Molecular Docking with Deep Learning Potentials." (Watch the talk)
• 5:00-5:30 JC Gumbart, Georgia Tech: "Conformational dynamics of HBV capsid proteins in free and drug-bound states." (Watch the talk)
• 5:30-6:00 Lingle Wang, Schrodinger: "Pushing the Boundaries of Free Energy Calculations." (Watch the talk)
• 6:00-6:30 Moderated Discussion on Grand Challenges in Free Energy Simulations by David Mobley - "It's like Deja Vu all over again."

Reception at Pagu hosted by Schrodinger (Pagu is located one block from Novartis at 310 Massachusetts Ave., Cambridge, MA)

Thursday, May 17th

• 8:30-9:00 Coffee and pastries
• 9:00-9:15 John Chodera, Welcome/Introduction (Watch the intro)
• 9:15-9:45 Greg Bowman: "Identifying and targeting excited states." (Watch the talk)
• 9:45-10:00 Simon Olsson: "Models of molecular kinetics driven by simulation and experiment." (Watch the talk)
• 10:00-10:15 Purushottam Dixit: "A maximum entropy based variational approach to manipulate Markov state models." (Watch the talk)
• 10:15-10:45 Coffee break
• 10:45-11:15 Vio Buchete: "Kinetic conformational networks for folding and protein-protein interactions: From amyloid peptides to kinase signaling." (Video available by request to speaker only)
• 11:15-11:30 Sonya Hanson: "What makes a kinase promiscuous for inhibitors?" (Requested not to be recorded)
• 11:30-11:45 Bryn Taylor: "Structural basis for ligand modulation of CCR2 activation pathways using Markov state models" (Watch the talk)
• 11:45-12:15 Benoit Roux: "Predicting the Conformational Variability of Abl tyrosine kinase using Molecular Dynamics Simulations and Markov State Models." (Watch the talk)

• 12:15-2:00 Lunch at Novartis

• 2:00-2:30 Dan Zuckerman: "Simple trajectory physics for path sampling and improving Markov models." (Video pending approval)
• 2:30-3:00 Justin Porter: "Exposons detect functionally-relevant conformational changes." (Watch the talk)
• 3:00-3:30 Chia-En Chang: "Modeling ligand-protein binding kinetics using molecular simulations." (Watch the talk)
• 3:30-4:00 Vince Voelz: "Markov State Model approaches to elucidate ligand binding mechanisms." (Watch the talk)
• 4:00-6:00 Poster session

Friday, May 18th

• 8:30-9:00 Coffee and pastries
• 9:00-9:30 Frank Noe: "Deep learning for molecular kinetics." (Watch the talk)
• 9:30-9:45 Maxwell Zimmerman: "Choice of adaptive sampling strategy impacts state discovery, transition probabilities, and the apparent mechanism of conformational changes." (Watch the talk)
• 9:45-10:00 Antonia Mey: "The role of fast motion in relation to catalysis in Cyclophilin variants." (Watch the talk. Corrupted audio, will be fixed later)
• 10:00-10:15 Jordi Juarez-Jimenez, U. of Edinburgh: "Computational and experimental approach for the detailed characterization of minor states in proteins: application to Cyclophilins loop dynamics." (Substitution to Rob Arbon) (Watch the talk, Corrupted audio, will be fixed later)
• 10:15-10:45 Coffee Break
• 10:45-11:15 Bettina Keller: "Girsanov reweighting for metadynamics simulations." (Requested not to be recorded)
• 11:15-11:30 Fabian Paul: "Estimating transitions rates of ultimate rare events using the transition-based reweighting analysis method." (Watch the talk)
• 11:30-12:00 Cecilia Clementi: "Incorporating experimental data in long-timescales macromolecular simulations" (Watch the talk)

• 12:00-1:30 Lunch at Novartis

• 1:30-2:00 Rebecca Wade: "Computationally efficient approaches to estimate drug-target binding kinetic parameters."
• 2:00-2:15 Zhifeng Jing: "Many-body effect determines the selectivity of Ca vs Mg in proteins."
• 2:15-2:30 Muneeb Sultan: "Using Markov state models to accelerate free-energy simulations."
• 2:30-3:00 Gianni de Fabritiis: "Simulations meet machine learning in structural biology."

Posters, Organizers and Code of Conduct

Poster should be 24" wide x 36" high. If you need to print your poster here, we recommend Cambridge Printing (http://cambridgeprinting.net/ ).

Poster Session 1 (Tuesday)

• Anna Pavlova, Georgia Tech: "Development of CHARMM-compatible parameters for cobalamins and other metal-containing cofactors."
• Jacob Litman, U. of Iowa: "Reweighting of Protein-Ligand Binding Simulations from Fixed Charge to Polarizable AMOEBA Thermodynamics."
• Joseph Bluck, Exeter: Absolute Free Energy Calculations to Guide Bromodomain Ligand Optimisation."
• Wei Chen: "A Novel Virtual Drug Screening Method with CDK8 as a Study Case."
• Sasmal Sukanya, UCI: "Alchemical free-energy calculations for predicting small molecule solubilities."
• Javier Caceres-Delpiano, U. of Southhampton, "Optimization of a Coarse-Grained Force Field based on experimental and atomistic simulation data."
• Alessio Lodola, Universita Degli Studi di Parma: "QM/MM-based simulations for the design of covalent inhibitors targeting EGFR."
• Daniel Cole, Newcastle U.: "Quantum Mechanics Based Potentials for Computer-Aided Drug Design."
• Yui Tik Pang: Georgia Tech: "The Role of Intramolecular Non-Bonded Interaction and Angle Sampling in Single Step Free Energy Perturbation."
• Hannah Bruce Macdonald, U. of Southhampton, Water networks and ligand binding free energies in protein-ligand complexes using Grand Canonical ensemble methods."
• Esteban Vöhringer-Martinez, Universidad de Concepción: "Atomic charges from from Atom-In-Molecules electron density partitioning methods validated for biomolecular free energy calculations."
• Yue Qian: "Force Field Evaluation on Absolute Free Energy of Binding Calculation Using a benchmark MIF system."
• Jonah Vilseck: U. of Michigan: "Validations and Applications of Multisite Lambda Dynamics in Drug Discovery."
• Cuchillo Rémi, UCB: "In-Silico Fragment Screening for PPI Inhibitor Discovery."
• Germano Heinzelmann, Universidade Federal de Santa Catarina: "APRprotein: Attach-pull-release calculations applied to bromodomains as a pose refinement and ligand ranking tool."
• Samaneh Mesbahi-Vasey: "Reaction coordinate for small molecule association with a protein binding site."
• Antonia Mey: "BioSimSpace -- How to write interoperable biomolecular simulation workflows."
• Zhi Wang, Washington U. in St. Louis, "AMOEBA Binding Calculations for SAMPL Host-Guest Systems"
• Stefan Doerr, Acellera, "ACEMD-ai: Ab-initio machine learning calculations of small molecules quantum energies and forces"

Poster Session 2 (Thursday)

• Giovanni Bottegoni, Heptares: "Metadynamics with Desmond and SuMTD to predict drug-GPCR kinetics."
• Anthony Hazel, Georgia Tech: "Folding free energy landscapes of β-sheets with non-polarizable and polarizable CHARMM force fields."
• Aniket Magarkar: "Combining Molecular Dynamics Simulations with Markov-State Models to Predict Binding Pose for Fragment on the Target Protein."
• Haoyu Yu, Schrodinger: "Accurate and Reliable Prediction of Irreversible Covalent Inhibitor Kinetics."
• Jordi Juarez-Jimenez, U. of Edinburgh, "Computational and experimental approach for the detailed characterisation of minor states in proteins: application to Cyclophilins loop dynamics." (Now giving talk on Friday)
• Mrinal Shekhar, U. of Illinois: "Structural Determinants of the IF-OF Transition in Human Glucose Transporters."
• Tim Hempel: "Unraveling Synaptotagmin-1 C2a conformational dynamics with local hidden Markov models and directed information."
• Davide Branduardi, Schrodinger: "Adiabatic Bias/Metadynamics Approach on Desmond GPU: High Throughput Residence Time Estimation."
• Cao Siqin: "ssYBG: a universal theory for calculating the solvent structures and solvation free energy of molecular solutes."
• Willem Jespers, "Structure based design of potent and selective ligands for the adenosine receptor family."
• Yu Zhou, National Institute of Biological Sciences: "Exploring Halogen Bonds in 5-Hydroxytryptamine 2B Receptor-Ligand Interactions."
• Stefania Evoli, IIT: "Metadynamics based studies of Brg1/DNA interactions."
• Cesar de Oliveira, "A Novel and Rigorous Free Energy Perturbation Approach to Estimate Binding Affinity of Ligands with Multiple Protonation States."
• Yunhui Ge, "Binding pathways of phenylalanine to the dimeric regulatory domain of human PAH reveal a lid gating mechanism."
• Samuel Lotz, Salotz: "Simulation, Visualization, and Analysis of an 11 min Timescale Drug Unbinding Process."
• Emel Ficici, NIH: "A Highly Conserved Sodium Binding Site in Prokaryotic Multi-drug Mate Transporters."
• Asaf Farhi, "Calculation of molecular free energies in classical potentials."
• Jose Jimenez: "Deep Learning based protein-ligand relative affinity prediction."
• Yun Luo, Western U.: "Predicting reversible covalent binding using two-state model."

Organizers

• John Chodera, Memorial-Sloan Kettering Cancer Center (john.chodera@choderalab.org)
• Greg Bowman, Washington University in St. Louis (bowman@biochem.wustl.edu)
• Callum Dickson, Novartis (callum.dickson@novartis.com)
• Jose Duca, Novartis (jose.duca@novartis.com)
• Viktor Hornak, Novartis (viktor.hornak@novartis.com)
• John Manchester, Novartis (john.manchester@novartis.com)
• Antonia Mey, University of Edinburgh (antonia.mey@ed.ac.uk)
• David Mobley, University of California at Irvine (dmobley@uci.edu)
• Michael Schnieders, The University of Iowa (michael-schnieders@uiowa.edu)
• Jana Shen, The University of Maryland (Jana.Shen@rx.umaryland.edu)
• Woody Sherman, Silicon Therapeutics (woody@silicontx.com)

We also thank current advisors and previous organizers:

• Brian McClain, Vertex (brian_mcclain@vrtx.com)
• Vijay Pande, Stanford University (pande@stanford.edu)
• Michael Shirts, University of Colorado Boulder (michael.shirts@colorado.edu)
• Camilo Velez-Vega, Entasis Therapeutics (camilo.velez@entasistx.com)

Conference Code of Conduct

All attendees, speakers, sponsors and volunteers at our conference are required to agree with the following code of conduct. Organisers will enforce this code throughout the event. We expect cooperation from all participants to help ensure a safe environment for everybody.

Need Help? Please contact the organising committee either in person or via email. Members of the organising committee are listed above.

The Quick Version

Our conference is dedicated to providing a harassment-free conference experience for everyone, regardless of gender, gender identity and expression, age, sexual orientation, disability, physical appearance, body size, race, ethnicity, religion (or lack thereof), or technology choices. We do not tolerate harassment of conference participants in any form. Sexual language and imagery is not appropriate for any conference venue, including talks, workshops, parties, Twitter and other online media. Conference participants violating these rules may be sanctioned or expelled from the conference without a refund at the discretion of the conference organisers.

The Less Quick Version

Harassment includes offensive verbal comments related to gender, gender identity and expression, age, sexual orientation, disability, physical appearance, body size, race, ethnicity, religion, technology choices, sexual images in public spaces, deliberate intimidation, stalking, following, harassing photography or recording, sustained disruption of talks or other events, inappropriate physical contact, and unwelcome sexual attention.

Participants asked to stop any harassing behavior are expected to comply immediately.

Sponsors are also subject to the anti-harassment policy. In particular, sponsors should not use sexualised images, activities, or other material. Booth staff (including volunteers) should not use sexualised clothing/uniforms/costumes, or otherwise create a sexualised environment.

If a participant engages in harassing behavior, the conference organisers may take any action they deem appropriate, including warning the offender or expulsion from the conference with no refund.

If you are being harassed, notice that someone else is being harassed, or have any other concerns, please contact a member of the organising committee immediately.

A member of the organising committee will be happy to help participants contact local law enforcement, provide escorts, or otherwise assist those experiencing harassment to feel safe for the duration of the conference. We value your attendance.

We expect participants to follow these rules at conference and workshop venues and conference-related social events.

The code of conduct text was taken from https://github.com/confcodeofconduct/confcodeofconduct.com in a slightly adapted form.