2014 Workshop on Free Energy Methods in Drug Design

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The 2014 Workshop on the State of Free Energy Calculations in Drug Design
Dates: May 19th-21st, 2014
Venue: Auditorium of Building 1, Vertex Pharmaceuticals Headquarers, Boston, MA (Fan Pier location)
50 Northern Avenue Boston, MA 02210


This workshop focuses on free energy techniques—the latest innovations and use cases, force field parameterization as it touches these techniques, and sampling practices, among other things. 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.


  • Kim Branson, Hessian Informatics email
  • John Chodera, Memorial-Sloan Kettering Cancer Center email
  • Richard Dixon, Vertex email
  • David Mobley, University of California-Irvine email
  • Vijay Pande, Stanford University email
  • Michael Shirts, University of Virginia email

Differences from previous workshops

We are hosting the workshop in a new venue: Vertex's auditorium in Boston, rather than at the Cambridge site. This means:

  • More room. Although the number of speakers will not change, the number of participants will be able to expand to approximately 90.
  • No confidentiality agreements. The auditorium is outside the "protected zone", which should hopefully allow a much bigger range of speakers.
  • We are also making a bigger effort to get more industry participation, with a goal that at least 1/3 of the talks are from industrial researchers.

Workshop format

There will be a number of talks spaced over three days, with ample time for discussion. We hope to draw talks on several main themes, including:

  1. Use cases for free energy techniques in real-world problems where they can or have had an impact;
  2. How pharma can best benefit today or in the immediate future;
  3. Parameterization of small molecules and proteins and how the latest innovations here affect free energies;
  4. Good sampling practices and challenges facing sampling and their impact on free energy estimates, and
  5. Design of experimental and simulation studies that could directly demonstrate the utility of free energy calculations in widespread industrial use.

Talks should be focused on addressing these or related aims. 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.


Monday, May 19

Monday Morning

Large scale free energy calculations (Moderator: Mike Schnieders)
8:00-8:30 Coffee and pastries
8:30-8:45 Welcome and Opening remarks
8:45-9:15 Jose Duca - "Reflections about protein flexibility, solvation, potency and binding kinetics in drug design"
9:15-9:45 Ron Levy - "Binding Free Energies on a Large Scale and Replica Exchange Sampling"
9:45-10:05 Coffee break
10:05-10:35 Alan Mark - "Single step perturbation approaches in ligand design and force field parameterization"
10:35-11:05 Robert Abel - "Free energy calculations in prospective drug discovery"
11:05-11:15 Brief coffee break
11:15-11:45 Clara Christ - "Free energy calculations – soon a standard tool in drug design?"
11:45-12:00 Floris Buelens - “Comparing Relative and Absolute Binding Free Energy Calculations for Inhibitors of Kinase PDK1”
12:00-1:30 Lunch (at Vertex)
12:30-1:30 Moderated lunchtime discussion: What is the state of free energy methods in drug design? What can we usefully discuss?
(Discussion leaders Michael Shirts and Clara Christ)

Monday Afternoon

And now for something completely different: Free energy alternatives to ‘alchemical’ calculations (Moderator: Vijay Pande)
1:30-2:00 R. Aldrin Denny - "Do relative free energy methods address drug design challenges? What do we need and where should our focus be?"
2:00-2:30 Enrico Purisima - "Estimating entropy from Quasi-Newton energy minimization"
2:30-2:50 Coffee
2:50-3:20 Gianni di Fabriitis - "In-silico ligand binding assays: poses, affinities and kinetics"
3:20-3:50 Chia-en Chang - "Free Energy Calculations for Modular Domain and Phosphopeptide Recognition"
3:50-4:10 Coffee
4:10-4:40 Vijay Pande - "What should we be predicting? Some arguments on where computation could be best applied in computational drug design
and some new methods to do it"
4:40-4:55 Gaetano Calabro - "Investigation of Non-Additivity in Protein-Ligand Binding"
4:55-5:30 Moderated afternoon discussion: What sort of pipelines and tools do we need to be building, both academic and industrial?
(Discussion leaders: Tom Woolf and Chris Bayly)
5:30-7:30 Poster Session

Tuesday, May 20

Tuesday Morning

I seen a lot in my time: Conformational sampling (Moderator: Ross Walker)
8:00-8:30 Coffee and pastries
8:30-9:00 Tom Woolf - "Pipelining conformational landscape searches and drug binding interactions:
a general framework using Python and Databases to control, analyze and stage large scale simulations"
9:00-9:30 Wei Yang - "Receptor-Ligand Binding Prediction in Explicit Solvent Environment"
9:30-9:50 Coffee
9:50-10:20 John Chodera - “Collecting the data we need to make progress”
10:20-10:50 David Minh - “Implicit Ligand Theory: Protein-Ligand Binding Free Energies for the Masses?
10:50-11:10 Coffee
11:10-11:40 Emilio Gallichio - “Extending Binding free energy calculations to large, flexible molecules
11:40-11:55 Daniel Cole - “Enhanced Monte Carlo Sampling through Replica Exchange with Solute Tempering”
11:55-1:30 Lunch (at Vertex)
12:30-1:30 Moderated lunchtime discussion: What sort of calculation standards, best practices and 'health' do we need?
(Discussion leaders: John Chodera and Robert Abel)

Tuesday afternoon

Dotting the i’s and crossing the t’s: Making free energy calculations robust (Moderator: John Chodera)
1:30-2:00 Benoit Roux - "Molecular Determinants of Kinase Inhibitor Specificity"
2:00-2:30 David Mobley - "Using solution-phase free energy calculations to improve binding free energies"
2:30-2:50 Coffee
2:50-3:20 Chris Oostenbrink - "Binding free energy calculations involving a net charge change"
3:20-3:50 Lingle Wang - "Important components in making FEP work"
3:50-4:10 Coffee
4:10-4:40 Huafeng Xu - "In search of dark free energy: Catching and resolving subtle errors in free energy calculations"
4:40-4:55 Gabe Rocklin - "How to accurately correct for periodicity artifacts in protein-ligand binding calculations on charged compounds"
4:55-5:30 Moderated afternoon discussion: What sort of experimental data sets and validation sets do we need?
(Discussion leaders: John Chodera and Paul Czodrowski)

Wednesday, May 21

Wednesday morning

Free energy calculations: Not just for binding any more! (Moderator: Michelle Hall)
8:00-8:30 Coffee and pastries
8:30-9 Phil Snyder - "The Potency-Insolubility Conundrum in Lead Optimization"
9:00-9:30 Chris Chipot - "Determination of lipid-bilayer permeabilities from first principles"
9:30-9:50 Coffee
9:50-10:20 Mike Schnieders - "Molecular Design Using Many-Body Physics"
10:20-10:50 JW Feng - "Ranking congeneric series with docking, MM/GBSA, and FEP -- a blinded study"
10:50-11:10 Coffee
11:10-11:40 Chris Bayly - "Using the unbound ligand free energy to answer important medicinal chemistry questions"
11:40-11:55 Chris Neale - "Identifying Hidden Free Energy Barriers"
11:55-1:30 Lunch (at Vertex)
12:30-1:30 Moderated lunchtime discussion: What sort of force fields and parameterizations are needed for effective drug design?
(Discussion Leaders: Vijay Pande and David Case)

Wednesday afternoon

Representing the system: Waters and force fields (Moderator: David Mobley)
1:30-2:00 Bernie Brooks - “Recent advances in hybrid quantum-chemical approaches for free energy simulations and constant pH simulations”
2:00-2:30 Paul Czodrowski - “To select fragments for kinase inhibitor design, decoration is key”
2:30-2:50 Coffee
2:50-3:20 Ross Walker - "Fast and Reliable Ligand Binding Free Energies - Thermodynamic Integration on GPUs"
3:20-3:50 Lars Sandberg - “Let’s be explicit about implicit solvent models”
3:50-4:10 Coffee
4:10-4:40 Michael Shirts - "Towards Best Practices in Protein-Ligand Binding Free Energies"
4:40-4:55 JC Gumbart - “Converging on an accurate description of water-membrane partitioning"
4:55-5:30 Moderated afternoon discussion: So what happens now? What are the next steps forward?
(Discussion Leaders: Michael Shirts and Jean-Francois Truchon)

Poster Session

The poster session will be directly adjacent to the auditorium in a multipurpose conference room. Posters can be up to 48 inches wide. They will be placed on a fabric walls (with pushpins) and other walls (with fun-tak mounting putty), which will be provided. The poster session room will be directly adjacent to the conference room, and people can set up their posters during lunch or other breaks on Monday.

Matteo Aldeghi Department of Biochemistry, University of Oxford Free energy of ligand binding to BRD4(1)
Kyle Beauchamp Memorial Sloan-Kettering Cancer Center Mapping Metastable States of the Human Kinome
David Case Dept. of Chemistry & Chemical Biology, Rutgers University Using 3D-RISM as an implicit solvent model for ligand binding studies.
Chia-en Chang Department of Chemistry, University of California, Riverside Ligand-protein Binding Free Energy Calculations: The Case of p38a MAP Kinase
Michel Cuendet Dept. of Physiology and Biophysics, Weill Cornell Medical College Enhanced sampling, free energy surface estimators, and force field validation
Paul Czodrowski Merck Darmstadt Chasing Protons
Nanjie Deng Dept. of Chemistry, Temple University Mechanisms of Drug Resistance Mutation in HIV-1 Integrase: Insights from Binding Free Energy Simulations
Christopher Fennell Department of Chemistry, Oklahoma State University Tuning force fields using liquid properties to sharpen free energy calculations
Marco Gallo University of San Luis Potosi Determination of the Free Energy of Solvation for Hydrogen Sulfide in Solvents Based on lmidazolium Ionic Liquids Using Molecular Simulations
JC Gumbart Department of Physics, Georgia Tech Parameterization of small (and large) molecules using the Force Field Toolkit
Kamran Haider Department of Chemistry, Lehman College, CUNY Towards and beyond solvent thermodynamics profiles of protein active sites
Michelle Hall Schrödinger Free energy perturbation for covalent inhibition
Sonya Hanson Memorial Sloan-Kettering Cancer Center Developing high-throughput fluorescence-based assays for measuring kinase inhibitor free energies of binding
Shuai Liu Department of Pharmaceutical Sciences, University of California, Irvine Lead optimization mapper: Automating free energy calculations for lead optimization
Viveca Lindahl KTH, Royal Institute of Technology A weighted histogram method for accelerating sampling
Lyna Luo Department of Pharmaceutical Sciences, Western University of Health Sciences Free energy calculation of connextin26 channel permeant and impermeant
Magnus Lundborg Department of Theoretical Physics, Royal Institute of Technology, Stockholm & SciLifeLab Stockholm Topology Generation, Solvation Free Energy Calculations and Improved Force Field Parameters
Justin McCallum SUNY-Stony Brook Biomolecular structures from limited experimental data
Yinglong Miao UC-San Diego Improved Reweighting of Accelerated Molecular Dynamics Simulations for Free Energy Calculation
Paulius Mikulskis Division of Theoretical chemistry, Department of Chemistry, Lund University A large-scale test of free-energy simulation estimates of protein ligand binding affinities
Okimasa OKADA Medicinal Chemistry Research Lab., Mitsubishi Tanabe Pharma Corp. Classification of crystal water molecules in protein binding site by free energy calculations
Levi Naden University of Virginia, Department of Chemical Engineering Linear basis function approach to efficient alchemical free energy calculations
Julia Park Department of Biomedical Engineering, University of Iowa Organic Crystal Thermodynamics using Polarizable Force Field based Alchemical Simulations
Daniel Parton Memorial Sloan-Kettering Cancer Center Deciphering ligand binding with alchemical free energy calculations, Markov state models, bioinformatics and high-throughput binding assays
Jan-Hendrik Prinz Memorial-Sloan Kettering Cancer Center, New York Paper-based micro well plates: Optimizing low volume fluorescence reading in protein-ligand binding measurements
David Rooklin Department of Chemistry, NYU Topographical mapping of protein surfaces to target PPI interfaces
Sandeep Somani Discovery Sciences, Janssen R&D, Spring House PA Free energy scoring of protein loops using replica exchange MD
Pin-Chih Su Center for Pharmaceutical Biotechnology, University of Illinois at Chicago The Impact of Effective Radii and Entropy on MM/PBSA, MM/GBSA, QM MM/GBSA Methods in Francisella tularensis Enoyl Acyl Reductase (FabI)
Lauren Wickstrom CUNY-Borough of Manhattan Community College Optimization of Protein-Ligand Binding Free Energy Models with Host-guest Affinity Data

The Venue: Getting There and Logistics

The conference will be in Auditorium of Building 1, Vertex headquarters <http://www.vrtx.com/boston-ma>, and 50 Northern Avenue, Boston, MA 02210 (phone number (617) 341-6100)

A NDA will not be required to enter the auditorium space on the 9th floor of Building 1, 50 Northern Avenue.

Getting there: The conference is at the Vertex Fan Pier location (http://www.fanpierboston.com/location/) This location is just across a public, outdoor parking lot from the Silver line Court House Station (dedicated MBTA high speed bus line connecting to the subway system).

Visitor Access

1) All Visitors should report to the Reception Desk at 50 Northern Avenue on each day of the workshop. The receptionist will ask for a photo identification before providing you with a visitor pass. Acceptable forms of identification are: driver's license, passport, or military ID. The visitor pass should be displayed while you're on site.

2) Visitors must be escorted at all times while they are on site. They cannot be allowed to wander at will to visit with other employees who may or may not be known to them or cause disruption in the workplace. Vertex's security team will have two dedicated elevators set aside for this meeting on the 9th Floor. Jean Francois Truchon, Kathleen O'Brien, and other volunteers will be available to assist during the meeting.

There will be wireless internet access, with the password given at the meeting.

Registration, lodging and meal costs

There is no registration fee. We regret that we are unable to provide funding for travel and lodging at this time. Vertex travel has agreed to help people find housing in the Boston area with a Vertex corporate discount. You can email VertexTravel@aexp.com or call at (866)-359-8789 to get assistance in booking a hotel room with this discount. They know to expect you: mention the Workshop on the State of Free Energy Calculations in Drug Design on May 19th - 21st.

If you are getting a hotel further out and driving in, parking information is available at https://www.fanpierboston.com/location/parking/, and will range from $35 to $20 for the day depending on when you leave. If you are taking public transport, Fan Pier is on the Silver Line (a high-speed, dedicated lane bus line).

Coffee and pastries as well as lunch will be provided at the venues on the days of the conference, and there will be vegetarian options. Schrodinger will be sponsoring refreshments for a poster session Monday evening.

Due to the logistical issues with this large a group, there will be no conference dinner with everyone together on Tuesday night; instead, we will organize groups to travel to various restaurants in the Boston area, with more details provided on the first day of the conference.

Nearby Restaurants

For each of these restaurants, we have reservations for 12 people each Tuesday night at varying times between 6 and 7. Sign up sheets are in the multipurpose room (audience's left). All restaurants without distances are within 0.4 miles. Please sign up before the end of the poster session!

Limoncello (Italian) http://www.ristorantelimoncello.com/ (1.6 miles) (directions)

Strega (seafood) http://www.stregawaterfront.com/ (directions)

Pastoral Fort Point (artisan pizza + bar) http://pastoralfortpoint.com/ (directions)

Sam's (modern) http://samsatlouis.com/ (directions)

Legal Test Kitchen (seafood) https://www.legalseafoods.com/restaurants/boston-legal-test-kitchen-br-seaport (directions)

Tavern Road (modern) http://tavernroad.com/ (directions)

Gather (modern) http://gatherboston.com/ (directions)

Alternatives without reservations: 14 restaurants at Faneuil Hall Marketplace (http://www.faneuilhallmarketplace.com/ (0.8 miles) (directions)


Event registration is now closed, as the event is filled to capacity, and speaking slots are filled. If there are particular compelling reasons that you should attend, please contact Michael Shirts (michael.shirts@virginia.edu).

Conference Participants

  • Robert Abel, Schrödinger
  • Matteo Aldeghi, University of Oxford
  • Mohammed AlQuraishi, Harvard
  • Chris Bayly, OpenEye
  • Kyle Beuchamp, Memorial Sloan-Kettering Cancer Center
  • Floris Buelens, Max Planck Institute for Biophysical Chemistry
  • Mark Brewer, Schrödinger
  • Bernie Brooks, NIH
  • Scott Brown, Sunivon
  • Gaetano Calabro, University of Edinburgh
  • Qing Cao, AstraZeneca
  • David Case, Rutgers
  • Chia-en Chang, UC-Riverside
  • Xin Chen, Novartis
  • Nicolas Cheron, Harvard
  • Chris Chipot, CNRS/University of Illinois at Urbana-Champaign
  • John Chodera, Memorial Sloan-Kettering Cancer Center
  • Clara Christ, Bayer Pharma AG
  • Danny Cole, Yale
  • Michel Cuendet, Cornell University Medical School
  • Jeremy Curusku, MIT
  • Paul Czodrowski, MerckSerono
  • Mihir Date, AstraZeneca
  • Gianni de Fabritiis, University Pompeu Fabra
  • Yuquing Deng, Schrödingerr
  • Nanjie Deng, Temple University
  • R. Aldrin Denny, Pfizer
  • Lenin Dominguez Ramirez, Universidad Autonoma Metropolitana at Lerma
  • Jose Duca, Novartis
  • Kristi Fan, Vitae Pharmaceuticals
  • John Faver, Yale
  • JW Feng, Genentech
  • Chris Fennell, Oklahoma State
  • Emilio Gallicchio, CUNY-Brooklyn
  • Marco Gallo, University of San Luis Potosi
  • Cen Gao, Lily
  • Paul Gibbons, Genetech
  • Andrei Golosov, Novartis
  • Patrick Grinway, Memorial Sloan-Kettering Cancer Center
  • JC Gumbart, Georgia Tech
  • Kamran Haider, CUNY-Lehman College
  • Michelle Hall, Schrödinger
  • Sonya Hanson, Memorial Sloan-Kettering Cancer Center
  • Ed Harder, Schrödinger
  • Anders Hogner, AstraZeneca
  • Viktor Hornak, Novartis
  • Xinjun Hou, Pfizer
  • Sunhwan Jo, University of Chicago
  • Ashutosh Jogalekar, Ensemble Therapeutics
  • Mitsunori Kato, Novartis
  • Byungchan Kim, Schrödinger
  • Bethany Kornos, Pfizer
  • Goran Krilov, Schrödinger
  • Tom Kurtzman, CUNY-Lehman College
  • Ron Levy, Rutgers University
  • Teng Lin, Schrödinger
  • Viveca Lindahl, KTH (Royal Institute of Technology)
  • Shuai Liu, UC-Irvine
  • Frank Lovering, Pfizer
  • Magnus Lundborg, KTH (Royal Institute of Technology)
  • Lyna Luo, Western University
  • Dmitry Lupyan, Schrödinger
  • John Manchester, AstraZeneca
  • Alan Mark, University of Queensland
  • Justin McCallum, SUNY-Stony Brook
  • Joe McDonald, Celgene
  • Daniel McKay, Novartis
  • Yinglong Miao, US-San Diego
  • Paulius Mikulskis, Lund University
  • David Minh, Illinois Institute of Technology
  • David Mobley, UC-Irvine
  • Levi Naden, University of Virginia
  • Chris Neale, RPI
  • Ana Newton, Yale
  • Okimasa OKADA, Mitsubishi Tanabe Pharma
  • Chris Oostenbrink, University of Natural Resources and Life Sciences, Vienna
  • Vijay Pande, Stanford University
  • Julia Park, University of Iowa
  • Danny Parton, Memorial Sloan-Kettering Cancer Center
  • Levi Pierce, Schrödinger
  • Jan-Hendrik Prinz, Memorial Sloan-Kettering Cancer Center
  • Enrico Purisima, National Research Council Canada
  • Salma Rafi, Memorial Sloan-Kettering Cancer Center
  • Vijayan Ramaswamy, Temple University
  • Michael Robertson, Yale
  • Gabe Rocklin, University of Washington
  • David Rooklin, New York University
  • Gregory Ross, University of Southampton
  • Benoit Roux, University of Chicago
  • Anatoly Ruvinsky, AstraZeneca
  • Lars Sandberg, University of Dundee
  • Jeffrey Sanders, Schrödinger
  • Michael Schnieders, University of Iowa
  • Michael Shirts, University of Virginia
  • Sarah Sirin, MIT
  • Chaya Stern, Memorial Sloan-Kettering Cancer Center
  • Terry Stouch, Science for Solutions
  • Pin-Chih Su, University of Illinois-Chicago
  • Rebecca Swett, Novartis
  • Jean-Francois Truchon, Vertex
  • John van Drie, Van Drie Research
  • Adrian Varela-Alvarez, AstraZeneca
  • Camilo Velez Vega, Novartis
  • Andreas Verras, Merck
  • Jonah Vilseck, Yale
  • Ross Walker, San Diego Supercomputer Center
  • Pat Walthers, Vertex
  • Lingle Wang, Schrödinger
  • Lauren Wickstrom, CUNY-Borough of Manhattan Community College
  • Sarah Williams, Novartis
  • Tom Woolf, Johns Hopkins
  • Yujie Wu, Schrödinger
  • Huafeng Xu, D. E. Shaw Research
  • Cindy Yan, Yale
  • Wei Yang, Florida State University
  • Ellen Zhong, University of Virginia