Difference between revisions of "2012 Workshop on Free Energy Methods in Drug Design"

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= 2012 Workshop on Free Energy Methods in Drug Design =
 
= 2012 Workshop on Free Energy Methods in Drug Design =
−
May 20-23, Cambridge, Massachusetts, USA
+
May 21-23, Cambridge, Massachusetts, USA
  
 
== Aims ==
 
== Aims ==
  
−
Since their first application decades ago, free energy methods have
+
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, the organizers, believe that these techniques are on the verge of being able to make an impact in appropriate drug discovery applications, but a number of challenges 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.  
−
promised great potential for revolutionizing the process of drug
 
−
discovery. Recent advances in computational power, new efficient
 
−
algorithms, and forcefield development efforts suggest that this
 
−
potential could soon be realized, but there remains a 'last mile'
 
−
problem in bringing these powerful techniques to the point where they
 
−
can play a significant role in driving drug discovery in both pharma
 
−
and academia.
 
  
−
To identify the remaining challenges and help foster a concerted
+
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.
−
effort to overcome them, we are organizing an intense workshop devoted
+
 
−
to bringing together experts from pharma and supporting industries, as
+
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 benefit today or in the immediate future; (3) parameterization and how the latest innovations here affect free energies; and (4) good sampling practices and challenges facing sampling and their impact on free energy estimates. 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.
−
well as from academia. The emphasis of this workshop will be on
+
 
−
identifying current challenges in the drug discovery process --
+
== Schedule Overview ==
−
specifically those where free energy methods might have the most
+
 
−
impact -- and determining the work that must be done as a community to
+
* Full days Monday, Tuesday, and Wednesday (contact D. Mobley if you are a presenter and will not be present for the whole meeting)
−
make free energy methods usable for these purposes.
+
* Conference dinner Monday night covered or subsidized by our sponsors (''note change of night'') at [http://firebrandsaints.com/ Firebrand Saints]
 +
* Poster session/mixer with food and drinks in the Vertex lobby on Tuesday night (''note change of night'')
  
 
== Organizers ==
 
== Organizers ==
−
* Kim Branson,  
+
* Kim Branson, Discovery Engine [mailto:kim@discoveryengine.com email]
 
* John Chodera, University of California, Berkeley [mailto:jchodera@berkeley.edu email]
 
* John Chodera, University of California, Berkeley [mailto:jchodera@berkeley.edu email]
−
* Richard Dixon, Vertex Pharmaceuticals  
+
* Richard Dixon, Vertex Pharmaceuticals [mailto:Richard_Dixon@vrtx.com email]
 
* David Mobley, University of New Orleans [mailto:dlmobley@uno.edu email]
 
* David Mobley, University of New Orleans [mailto:dlmobley@uno.edu email]
 
* Vijay Pande, Stanford University [mailto:pande@stanford.edu email]
 
* Vijay Pande, Stanford University [mailto:pande@stanford.edu email]
 
* Michael Shirts, University of Virginia [mailto:michael.shirts@virginia.edu email]
 
* Michael Shirts, University of Virginia [mailto:michael.shirts@virginia.edu email]
 +
 +
==Talks ==
 +
 +
In keeping with the (popular) format of our previous workshop, typical talks will be 25 minutes in length plus a few minutes for questions.
 +
 +
While this is a short format, it is in keeping with the goals of the workshop: We're after focused talks which highlight a particularly informative study or aspect in the area, not an overview of everything you've done in the field.  Example topics might include:
 +
* An unresolved puzzle relating to a free energy study in some particular system
 +
* Sampling challenges facing application of free energy methods to a particular system, and ideas how to tackle these
 +
* A new sampling method and how it has been applied to resolve sampling problems in free energy calculations
 +
* Why free energy calculations for target X reliably crash and burn, but target Y seems much more tractable
 +
 +
Many others are possible. The point is, we're not after a sales pitch for free energy methods -- we like them already! -- we want to hear what you find works, what doesn't work, and what you know or think about why.
 +
 +
== Sponsors and Sponsorships ==
 +
 +
[http://www.chemcomp.com CCG] is generously sponsoring a conference dinner. Thank you, CCG!
 +
[http://www.schrodinger.com/ Schrödinger] is sponsoring our poster session, with food and drinks. Thank you, Schrödinger!
 +
[http://www.stonybrook.edu/commcms/laufer/ The Laufer Center] at Stony Brook University is also providing financial support for the meeting. Thank you, Laufer Center!
 +
 +
If your organization is interested in sponsoring, please contact [mailto:dlmobley@uno.edu David Mobley].
  
 
== Support ==
 
== Support ==
−
Contact for travel arrangements, lodging, and general questions about Cambridge:
+
Contact for travel arrangements, lodging, and general questions about Cambridge: Richard Dixon, Vertex Pharmaceuticals [mailto:Richard_Dixon@vrtx.com email] (CC D. Mobley)
−
* TBA
 
  
 
== Date and Location ==
 
== Date and Location ==
−
May 20-23, 2011<br />
+
May 21-23, 2012<br />
−
675 Kendall St [[http://www.kendallsquare.org/675kendall.html info] | [http://www.kendallsquare.org/directions.html parking] | [http://www.vrtx.com/destination-vertex/locations/cambridge.html directions] | [http://maps.google.com/maps?f=q&source=s_q&hl=en&geocode=&q=675+kendall+st,+cambridge,+ma&sll=42.36395,-71.0813&sspn=0.010147,0.022724&gl=us&ie=UTF8&hq=&hnear=Kendall+St,+Cambridge,+Middlesex,+Massachusetts+02142&z=16 Google maps]] (Kendall Lecture Hall, 3rd floor)<br />  
+
675 Kendall St [[http://www.kendallsquare.org/675kendall.html info] | [http://www.kendallsquare.org/directions.html parking] | [http://www.vrtx.com/destination-vertex/locations/cambridge.html directions] | [http://maps.google.com/maps?f=q&source=s_q&hl=en&geocode=&q=675+kendall+st,+cambridge,+ma&sll=42.36395,-71.0813&sspn=0.010147,0.022724&gl=us&ie=UTF8&hq=&hnear=Kendall+St,+Cambridge,+Middlesex,+Massachusetts+02142&z=16 Google maps]] <br />  
 
Cambridge, MA<br />
 
Cambridge, MA<br />
  
−
The meeting will take place in the Kendall Lecture Hall in the Vertex space on the third floor of 675 West Kendall.
+
Attendees should proceed to the lobby of the Vertex building at 675 West Kendall in Cambridge.  Security will meet you for registration and CDA signing. Attendees will then be escorted to the Lecture Hall on the third floor.  Breakfast is in a satellite meeting room next to the lecture hall.  Registration and escort will also be necessary on Tuesday and Wednesday, but just one CDA will cover the whole conference.
−
 
 
−
On entering 675 West Kendall Street, there will be a sign-in table in the main lobby.  After signing in and receiving a Visitor Pass, take the elevator to the third floor. There will be a security officer at the elevators on the third floor who will check your Visitor Pass.  Proceed to the Kendall Lecture Hall, located inside the Vertex space and to the right.
 
  
−
Passes should be relinquished on leaving Vertex each evening.
+
''The conference site will have wireless internet access via a guest password. Cell phone reception will likely be spotty in the lecture hall.''
−
 
 
−
''The conference site will have wireless internet access via a guest password.''
 
  
 
== Fees ==
 
== Fees ==
Line 52: Line 61:
 
== Workshop Format ==
 
== Workshop Format ==
  
−
There will be a number of talks with ample time for discussion.  
+
There will be a number of talks 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 benefit today or in the immediate future; (3) parameterization and how the latest innovations here affect free energies; and (4) good sampling practices and challenges facing sampling and their impact on free energy estimates. 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. Discussion of failures are encouraged!
−
The workshop will be highly focused on (1) identifying the particular opportunities where free energy methods can have an impact on drug discovery, (2) enumerating the challenges remaining before free energy methods can find widespread use in ligand and drug design, and (3) facilitating the organization of 'working groups' to aid in tackling various aspects of these challenges after the meeting has concluded.  
 
−
Talks should be focused on addressing these (or related) aims.
 
−
For example, 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.
 
−
Discussion of failures are encouraged!
 
−
 
 
−
Three kinds of presentations will be available, with ample time for discussion allotted.
 
−
* '''25-minute talks''' to highlight some of the above issues encountered in work or present new tools
 
−
* '''10-minute talks''' to give brief updates on projects or inspire discussion about questions
 
−
* '''poster presentations''' (encouraged for attending students or highlighting issues or methods in more detail)
 
  
−
== Deadlines ==
+
== Attending the meeting ==
  
−
TBA
+
Registration is currently closed. Please contact David Mobley if you would like to be on a waiting list in case additional slots open up.
  
 
== Lodging and meals ==
 
== Lodging and meals ==
  
 
* Coffee, lunch, and beverages will be provided at Vertex.
 
* Coffee, lunch, and beverages will be provided at Vertex.
−
* We regret that we are unable to provide funding for travel and lodging, but you may use the Vertex Transient Room Rate at the [http://www.sonesta.com/Boston/ Royal Sonesta Hotel, Cambridge, MA] ([http://www.yelp.com/biz/royal-sonesta-hotel-cambridge yelp] | [http://www.tripadvisor.com/Hotel_Review-g60890-d89644-Reviews-Royal_Sonesta_Hotel_Boston-Cambridge_Massachusetts.html tripadvisor]), close to Vertex (Vertex is located at 675 W Kendall St.)
+
* A conference dinner is generously being sponsored by CCG and the Laufer Center for Quantitative Biology.
 +
* Vertex has arranged for a block of rooms at a discounted rate ($179 per night plus tax), at the Hyatt Cambridge about 2 miles from the meeting:
 +
  [http://cambridge.hyatt.com/hyatt/hotels/index.jsp?null Hyatt Regency Cambridge]
 +
  575 Memorial Drive,
 +
  Cambridge, Massachusetts, USA 02139-4896
 +
 
 +
 
 +
For reservations, please call Vertex Travel:
 +
 
 +
  Reservations can be made by calling Vertex travel -- as soon as possible as rooms may sell out
 +
  617-444-6225
 +
  Please reference "Dixon - ENERGY"
 +
  Reservations must be made at the time of the call.
 +
  Reservations will be made using each individual's Credit Card account number.
 +
  Anyone using this option will be responsible for all fees and/or cancellation or no-show penalties if incurred.
 +
  Cancellation policy is '''30 days''' prior to arrival -- by calling the hotel directly. (This unusual cancellation policy is apparently due to commencement season).
 +
 
 +
== Schedule ==
  
−
  The Royal Sonesta Hotel
+
A tentative draft schedule follows. Normal talks are 25 minutes + 5 minutes for questions. Some slots for short talks are available; these are 15 minutes + 5 minutes for questions. If you are interested in giving a short talk please submit a proposed abstract and title to David Mobley, dlmobley - at - uno - dot -edu, as soon as possible. Short talks will be selected from submitted abstracts.
−
  40 Edwin Land Boulevard
 
−
  Cambridge, MA 02142
 
−
  617-806-4200
 
  
−
Please request the VERTEX RATE covering any combination of the nights of May 16 – May 19 inclusive:
+
=== Monday, May 21===
  
−
  STANDARD ROOM: $185 + tax per room per night.
+
'''Monday morning:'''
−
  DELUXE ROOM (view of the Charles River): $235 + tax per room per night. 
 
  
−
May is high season in Boston and Cambridge (tourists, graduations, etc.) so please call and make your reservations as soon as possible.
+
  "War games: Model systems"
 +
  David Mobley, moderator
 +
    7:45-8:15: Coffee and pastries
 +
    8:15-8:30: Opening remarks (Richard Dixon, Vertex)
 +
    8:30-9: Mark Murcko [25 min ] - TBA
 +
    9-9:30: Anita de Ruiter [ 25 min ] - "Efficient and accurate free energy calculations on trypsin inhibitors"
 +
    9:30-9:50: Coffee break [ 20 min ]
 +
    9:50-10:20: Gabriel Rocklin  [ 25 min ] - "Testing alchemical free energy calculations in a charged model site"
 +
    10:20-10:50:  Hari Muddana [ 25 min ] - "Binding affinities of host-guest systems using QM energy models"
 +
    10:50-11:10: Coffee break [ 20 min ]
 +
    11:10-11:40:  Richard Dixon [ 25 min ] - "Vertex sets for method testing"
 +
    11:40-12: David Mobley - moderated discussion
  
−
To make a reservation using the VERTEX RATE:
+
'''Lunch at Vertex: 12-1'''
  
−
  Call the Royal Sonesta Hotel direct 617-806-4200; or
+
'''Monday afternoon:'''
−
  Call the Vertex Travel Dept: 617-44-6225; or
 
−
  Have your travel agency book the VERTEX RATE.
 
  
−
Cancellation policy for The Royal Sonesta Hotel is:
+
  "Validation and application"
 +
  John Chodera, moderator
 +
    1-1:30: Michael Shirts [ 25 min ] - "Validation efforts and efficiency improvements in free energy calculations"
 +
    1:30-2: Clara Christ  [ 25 min ] - "Free energy calculations as a tool in drug discovery"
 +
    2-2:20: Coffee break [ 20 min ]
 +
    2:20-2:50: Marc Bianciotto [ 25 min ] - "Determination of the mode of action of FGFR ECD allosteric modulators"
 +
    2:50-3:20:  Julien Michel [ 25 min ] - "Challenges and bottlenecks in applying free energy calculations in structure-based drug design"
 +
    3:20-3:40: Coffee break [ 20 min ]
 +
    3:40-4:10: Gianni de Fabritiis  [ 25 min ] - "Fragment-based drug design using molecular dynamics"
 +
    4:10-4:40: Chia-En Chang [ 25 min ] - "Insights from Free Energy Calculations: Protein Conformational Equilibrium, Driving Forces and Ligand Binding Modes"
 +
    4:40-5:00: John Chodera - moderated discussion
 +
   
  
−
  By 6 PM, 24 hours prior to date of arrival.  
+
'''Conference dinner sponsored by [http://www.chemcomp.com/ CCG] and the [http://laufercenter.stonybrook.edu/ Laufer Center], 5:30-8:30 p.m. at [http://firebrandsaints.com/ Firebrand Saints ], One Broadway, Cambridge, MA. (Google Map for walking: [http://g.co/maps/p9qf7 map])'''
  
−
The hotel is a 7-12 minute walk to the Vertex site.  The hotel can provide complimentary shuttle service, so please inquire at GUEST SERVICES for available times to use the 14-passenger van to the meeting.
+
=== Tuesday, May 22===
  
−
== Schedule ==
+
'''Tuesday morning:'''
 +
 
 +
  "Parameterization, force fields, and methodology"
 +
  Vijay Pande, moderator
 +
    7:45-8:30: Coffee and pastries
 +
    8:30-9: Charles L. Brooks, III [ 25 min ] - "Extended Lagrangian Methods for Free Energy Based Simulations"
 +
    9-9:30: David Cerutti [ 25 min ] - "Using free energy to update force fields"
 +
    9:30-9:50: Coffee break [ 20 min ]
 +
    9:50-10:20: John Chodera  [ 25 min ] - "Redesigning drug design"
 +
    10:20-10:50: Michael Schnieders [ 25 min ] - "Accelerating polarizable multipole AMOEBA free energy calculations using orthogonal space methods"
 +
    10:50-11:10: Coffee break [ 20 min ]
 +
    11:10-11:40:  Emilio Gallicchio [ 25 min ] - "Binding pathways, conformational sampling, and convergence: the shortest route is often not the fastest"
 +
    11:40-12: Vijay Pande - moderated discussion
 +
 
 +
'''Lunch at Vertex: 12-1'''
 +
 
 +
'''Tuesday afternoon:'''
 +
 
 +
  "You mean, we can use free energies for other things, too? Bound waters, permeation, and solubilities"
 +
  Gabriel Rocklin, moderator
 +
    1-1:30: Jonathan Essex [ 25 min ] - "Free energy calculations of the role of bound water in protein-ligand association"
 +
    1:30-2: Guanglei Cui [ 25 min ] - "SPAM: a simple approach of profiling bound water molecules and its application in lead optimization"
 +
    2-2:20: Coffee break [ 20 min ]
 +
    2:20-2:50: Jean-Francois Truchon [ 25 min ] - "What can we learn from integral equation theory: Using 3D-RISM free energies in modeling"
 +
    2:50-3:20:  Rommie Amaro [ 25 min ] - "Small molecule membrane permeability"
 +
    3:20-3:40: Coffee break [ 20 min ]
 +
    3:40-4:10:  Andrew Paluch [ 25 min ] - "Solubility prediction using free energy calculations and thermodynamic modeling"
 +
    4:10-4:30: Gabriel Rocklin - moderated discussion
 +
    4:30-4:50: David Borhani [ 15 min ] - "Using Anton to study GPCR-ligand binding"
 +
    4:50-5:10: Rob Rizzo [ 15 min ] - "Application of Approximate Free Energy Methods to Estimate Drug Resistance"
 +
 
 +
'''Poster session, mixer, and food -- Vertex lobby, 5:30-7:30 p.m.'''
 +
 
 +
=== Wednesday, May 23===
 +
 
 +
'''Wednesday morning:'''
 +
 
 +
  "Relative free energy calculations"
 +
  Michael Shirts, moderator
 +
    7:45-8:30: Coffee and pastries
 +
    8:30-9: Robert Abel [ 25 min ] - "Relative binding free energy calculations for medicinally interesting targets including comparisons with alternative approaches"
 +
    9-9:30: David Mobley [ 25 min ] - "Planning and conducting relative free energy calculations -- automation and issues"
 +
    9:30-9:55: Coffee break [ 25 min ]
 +
    9:55-10:25: Demetri Moustakas  [ 25 min ] - "Towards a single-point estimate of the binding free energy"
 +
    10:25-10:55: Lingle Wang [ 25 min ] - "Combination of enhanced sampling techniques into FEP to get structural reorganization effects in relative binding affinity calculations"
 +
    10:55-11:20: Coffee break [ 25 min ]
 +
    11:20-11:40:  Gerhard König  [ 15 min ] -- "Enhanced sampling in free energy calculations with SGLD"
 +
    11:40-12:00: Michael Shirts - moderated discussion
  
−
TBA
+
'''Lunch at Vertex: 12:00-1'''
  
−
== Speakers ==
+
'''Wednesday afternoon:'''
  
−
TBA
+
  "Proteins aren't rocks -- they wiggle! Conformational changes and non-alchemical approaches"
 +
  Richard Dixon, moderator
 +
    1-1:30: Denis Bucher [ 25 min ] - "Using Accelerated MD to Characterize Long Time-Scales in Proteins and Estimate the Reorganization Free energy upon Ligand Binding"
 +
    1:30-2: Vijay Pande [ 25 min ] - "Combining Markov State Models with Free Energy Calculations for Allostery"
 +
    2-2:20: Coffee break [ 20 min ]
 +
    2:20-2:50: Tom Woolf [ 25 min ] - "Exchange Protein Activated by cAMP (EPAC): Transitions in Allosteric Binding"
 +
    2:50-3:20:  Christophe Chipot [ 25 min ] - "Calculations of standard binding free energies using adaptive biasing forces"
 +
    3:20-3:40: Coffee break [ 20 min ]
 +
    3:40-4:10: Michel Cuendet  [ 25 min ] - Adiabatic Free Energy Dynamics
 +
    4:10-4:30: Richard Dixon - moderated discussion
 +
    4:30-4:50: Hideaki Fujitani [ 15 min ] - "Molecular dynamics simulations with FUJI force field"
 +
    4:50-5:10: Hironori Kokubo  [ 15 min ] - "Prediction of Protein-Ligand Binding Structures by Generalized-Ensemble Simulation"
  
−
== Non-speaking attendees ==
+
== Non-speaking attendees (poster presenters indicated) ==
  
−
TBA
+
* Allen, William (Stony Brook University) '''Poster'''
 +
* Borhani, David (D. E. Shaw)
 +
* Branson, Kim (Discovery Engine)
 +
* Brown, Scott (Sunivion).
 +
* Case, David (Rutgers)
 +
* Campbell, Arthur (AstraZeneca)
 +
* Cheng, Alan (Amgen) '''Poster'''
 +
* Chin, Donovan (Novartis)
 +
* Curuksu, Jeremy (MIT)
 +
* Deng, Nanjie (Rutgers)
 +
* Denny, R. Aldrin (Pfizer)
 +
* Dill, Ken A. (Stony Brook University)
 +
* Fochtman, Brian (Stony Brook University) '''Poster'''
 +
* Gao, Cen (Eli Lilly)
 +
* Guilbert, Christophe (UCSF)
 +
* Hempel, Judith (Duke University)
 +
* Hidresh, Kumar (IIT, Delhi, India) '''Poster'''
 +
* Huang, Yulin (Stony Brook University) '''Poster'''
 +
* Jiang, Lingling (Stony Brook University) '''Poster'''
 +
* Kato, Mitsunoori (Novartis)
 +
* Kim, Byungchan (Schrodinger)
 +
* Kumar, Hirdesh (Indian Institute of Technology) '''Poster'''
 +
* Labute, Paul (CCG)
 +
* Lamb, Michelle (AstraZeneca)
 +
* Lawrenz, Morgan (Stanford University) '''Poster'''
 +
* Lin, Teng (Schrödinger)
 +
* Mahboobi, S. Hanif (Berkeley) '''Poster'''
 +
* McKay, Dan (Novartis)
 +
* Miller, Matthew (AstraZeneca)
 +
* Okada, Okimasa (Mitsubishi Tanabe Pharma) '''Poster'''
 +
* Parameswarn, Sreeja (University of New Orleans) '''Poster'''
 +
* Paulino, Margot (UdelaR) '''Poster'''
 +
* Sanders, Jeffrey (Thomas Jefferson University) '''Poster'''
 +
* Shams, Hengameh (Berkeley) '''Poster'''
 +
* Shi, Yue (University of Texas, Austin)
 +
* Shriram, Purohit (S.E.T. College of Pharmacy, Dharwad, India) '''Poster'''
 +
* Stouch, Terry (Science for Solutions, LLC) '''Poster'''
 +
* Swift, Robert (University of California, San Diego) '''Poster'''
 +
* Tsui, Vickie (Genentech)
 +
* Wickstrom, Lauren (Rutgers) '''Poster'''
 +
* Wu, Yujie (Schrödinger)
 +
* Zheng, Zhong (St. Jude Children's Research Hospital) '''Poster'''
 +
* Zunini, Margot Paulino (Universidad de la República, Uruguay) '''Poster'''
  
 
== Restaurants in Boston ==
 
== Restaurants in Boston ==
Line 116: Line 249:
 
* [http://www.helmandrestaurantcambridge.com/ Helmand]
 
* [http://www.helmandrestaurantcambridge.com/ Helmand]
 
* [http://www.brownsugarcafe.com/ The Similians]
 
* [http://www.brownsugarcafe.com/ The Similians]
 +
* [http://www.hungrymothercambridge.com/ Hungry Mother] [http://www.yelp.com/biz/hungry-mother-cambridge (yelp)]
  
 
=== Directions from Cambridge to Boston ===
 
=== Directions from Cambridge to Boston ===

Latest revision as of 21:22, 21 May 2012

2012 Workshop on Free Energy Methods in Drug Design

May 21-23, Cambridge, Massachusetts, USA

Aims

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, the organizers, believe that these techniques are on the verge of being able to make an impact in appropriate drug discovery applications, but a number of challenges 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.

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 benefit today or in the immediate future; (3) parameterization and how the latest innovations here affect free energies; and (4) good sampling practices and challenges facing sampling and their impact on free energy estimates. 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.

Schedule Overview

  • Full days Monday, Tuesday, and Wednesday (contact D. Mobley if you are a presenter and will not be present for the whole meeting)
  • Conference dinner Monday night covered or subsidized by our sponsors (note change of night) at Firebrand Saints
  • Poster session/mixer with food and drinks in the Vertex lobby on Tuesday night (note change of night)

Organizers

  • Kim Branson, Discovery Engine email
  • John Chodera, University of California, Berkeley email
  • Richard Dixon, Vertex Pharmaceuticals email
  • David Mobley, University of New Orleans email
  • Vijay Pande, Stanford University email
  • Michael Shirts, University of Virginia email

Talks

In keeping with the (popular) format of our previous workshop, typical talks will be 25 minutes in length plus a few minutes for questions.

While this is a short format, it is in keeping with the goals of the workshop: We're after focused talks which highlight a particularly informative study or aspect in the area, not an overview of everything you've done in the field. Example topics might include:

  • An unresolved puzzle relating to a free energy study in some particular system
  • Sampling challenges facing application of free energy methods to a particular system, and ideas how to tackle these
  • A new sampling method and how it has been applied to resolve sampling problems in free energy calculations
  • Why free energy calculations for target X reliably crash and burn, but target Y seems much more tractable

Many others are possible. The point is, we're not after a sales pitch for free energy methods -- we like them already! -- we want to hear what you find works, what doesn't work, and what you know or think about why.

Sponsors and Sponsorships

CCG is generously sponsoring a conference dinner. Thank you, CCG! Schrödinger is sponsoring our poster session, with food and drinks. Thank you, Schrödinger! The Laufer Center at Stony Brook University is also providing financial support for the meeting. Thank you, Laufer Center!

If your organization is interested in sponsoring, please contact David Mobley.

Support

Contact for travel arrangements, lodging, and general questions about Cambridge: Richard Dixon, Vertex Pharmaceuticals email (CC D. Mobley)

Date and Location

May 21-23, 2012
675 Kendall St [info | parking | directions | Google maps]
Cambridge, MA

Attendees should proceed to the lobby of the Vertex building at 675 West Kendall in Cambridge. Security will meet you for registration and CDA signing. Attendees will then be escorted to the Lecture Hall on the third floor. Breakfast is in a satellite meeting room next to the lecture hall. Registration and escort will also be necessary on Tuesday and Wednesday, but just one CDA will cover the whole conference.

The conference site will have wireless internet access via a guest password. Cell phone reception will likely be spotty in the lecture hall.

Fees

There is no registration fee for this workshop.

Workshop Format

There will be a number of talks 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 benefit today or in the immediate future; (3) parameterization and how the latest innovations here affect free energies; and (4) good sampling practices and challenges facing sampling and their impact on free energy estimates. 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. Discussion of failures are encouraged!

Attending the meeting

Registration is currently closed. Please contact David Mobley if you would like to be on a waiting list in case additional slots open up.

Lodging and meals

  • Coffee, lunch, and beverages will be provided at Vertex.
  • A conference dinner is generously being sponsored by CCG and the Laufer Center for Quantitative Biology.
  • Vertex has arranged for a block of rooms at a discounted rate ($179 per night plus tax), at the Hyatt Cambridge about 2 miles from the meeting:
  Hyatt Regency Cambridge
  575 Memorial Drive,
  Cambridge, Massachusetts, USA 02139-4896

For reservations, please call Vertex Travel: 

  Reservations can be made by calling Vertex travel -- as soon as possible as rooms may sell out
  617-444-6225 
  Please reference "Dixon - ENERGY"
  Reservations must be made at the time of the call.
  Reservations will be made using each individual's Credit Card account number.
  Anyone using this option will be responsible for all fees and/or cancellation or no-show penalties if incurred.
  Cancellation policy is 30 days prior to arrival -- by calling the hotel directly. (This unusual cancellation policy is apparently due to commencement season).

Schedule

A tentative draft schedule follows. Normal talks are 25 minutes + 5 minutes for questions. Some slots for short talks are available; these are 15 minutes + 5 minutes for questions. If you are interested in giving a short talk please submit a proposed abstract and title to David Mobley, dlmobley - at - uno - dot -edu, as soon as possible. Short talks will be selected from submitted abstracts.

Monday, May 21

Monday morning: 

 "War games: Model systems"
  David Mobley, moderator
    7:45-8:15: Coffee and pastries
    8:15-8:30: Opening remarks (Richard Dixon, Vertex)
    8:30-9: Mark Murcko [25 min ] - TBA
    9-9:30: Anita de Ruiter [ 25 min ] - "Efficient and accurate free energy calculations on trypsin inhibitors"
    9:30-9:50: Coffee break [ 20 min ]
    9:50-10:20: Gabriel Rocklin  [ 25 min ] - "Testing alchemical free energy calculations in a charged model site"
    10:20-10:50:   Hari Muddana [ 25 min ] - "Binding affinities of host-guest systems using QM energy models"
    10:50-11:10: Coffee break [ 20 min ]
    11:10-11:40:  Richard Dixon [ 25 min ] - "Vertex sets for method testing"
    11:40-12: David Mobley - moderated discussion

Lunch at Vertex: 12-1

Monday afternoon: 

 "Validation and application"
  John Chodera, moderator
    1-1:30: Michael Shirts [ 25 min ] - "Validation efforts and efficiency improvements in free energy calculations"
    1:30-2: Clara Christ  [ 25 min ] - "Free energy calculations as a tool in drug discovery"
    2-2:20: Coffee break [ 20 min ]
    2:20-2:50: Marc Bianciotto [ 25 min ] - "Determination of the mode of action of FGFR ECD allosteric modulators"
    2:50-3:20:  Julien Michel [ 25 min ] - "Challenges and bottlenecks in applying free energy calculations in structure-based drug design"
    3:20-3:40: Coffee break [ 20 min ]
    3:40-4:10: Gianni de Fabritiis  [ 25 min ] - "Fragment-based drug design using molecular dynamics"
    4:10-4:40: Chia-En Chang [ 25 min ] - "Insights from Free Energy Calculations: Protein Conformational Equilibrium, Driving Forces and Ligand Binding Modes"
    4:40-5:00: John Chodera - moderated discussion

Conference dinner sponsored by CCG and the Laufer Center, 5:30-8:30 p.m. at Firebrand Saints , One Broadway, Cambridge, MA. (Google Map for walking: map)

Tuesday, May 22

Tuesday morning: 

 "Parameterization, force fields, and methodology"
  Vijay Pande, moderator
    7:45-8:30: Coffee and pastries
    8:30-9: Charles L. Brooks, III [ 25 min ] - "Extended Lagrangian Methods for Free Energy Based Simulations"
    9-9:30: David Cerutti [ 25 min ] - "Using free energy to update force fields" 
    9:30-9:50: Coffee break [ 20 min ]
    9:50-10:20: John Chodera  [ 25 min ] - "Redesigning drug design"
    10:20-10:50: Michael Schnieders [ 25 min ] - "Accelerating polarizable multipole AMOEBA free energy calculations using orthogonal space methods"
    10:50-11:10: Coffee break [ 20 min ]
    11:10-11:40:  Emilio Gallicchio [ 25 min ] - "Binding pathways, conformational sampling, and convergence: the shortest route is often not the fastest"
    11:40-12: Vijay Pande - moderated discussion

Lunch at Vertex: 12-1

Tuesday afternoon: 

 "You mean, we can use free energies for other things, too? Bound waters, permeation, and solubilities"
 Gabriel Rocklin, moderator
    1-1:30: Jonathan Essex [ 25 min ] - "Free energy calculations of the role of bound water in protein-ligand association"
    1:30-2: Guanglei Cui [ 25 min ] - "SPAM: a simple approach of profiling bound water molecules and its application in lead optimization"
    2-2:20: Coffee break [ 20 min ]
    2:20-2:50: Jean-Francois Truchon [ 25 min ] - "What can we learn from integral equation theory: Using 3D-RISM free energies in modeling"
    2:50-3:20:  Rommie Amaro [ 25 min ] - "Small molecule membrane permeability"
    3:20-3:40: Coffee break [ 20 min ]
    3:40-4:10:  Andrew Paluch [ 25 min ] - "Solubility prediction using free energy calculations and thermodynamic modeling"
    4:10-4:30: Gabriel Rocklin - moderated discussion
    4:30-4:50: David Borhani [ 15 min ] - "Using Anton to study GPCR-ligand binding"
    4:50-5:10: Rob Rizzo [ 15 min ] - "Application of Approximate Free Energy Methods to Estimate Drug Resistance"

Poster session, mixer, and food -- Vertex lobby, 5:30-7:30 p.m.

Wednesday, May 23

Wednesday morning: 

 "Relative free energy calculations"
  Michael Shirts, moderator
    7:45-8:30: Coffee and pastries
    8:30-9: Robert Abel [ 25 min ] - "Relative binding free energy calculations for medicinally interesting targets including comparisons with alternative approaches"
    9-9:30: David Mobley [ 25 min ] - "Planning and conducting relative free energy calculations -- automation and issues"
    9:30-9:55: Coffee break [ 25 min ]
    9:55-10:25: Demetri Moustakas  [ 25 min ] - "Towards a single-point estimate of the binding free energy" 
    10:25-10:55: Lingle Wang [ 25 min ] - "Combination of enhanced sampling techniques into FEP to get structural reorganization effects in relative binding affinity calculations"
    10:55-11:20: Coffee break [ 25 min ]
    11:20-11:40:  Gerhard König  [ 15 min ] -- "Enhanced sampling in free energy calculations with SGLD"
    11:40-12:00: Michael Shirts - moderated discussion

Lunch at Vertex: 12:00-1

Wednesday afternoon: 

 "Proteins aren't rocks -- they wiggle! Conformational changes and non-alchemical approaches"
 Richard Dixon, moderator
    1-1:30: Denis Bucher [ 25 min ] - "Using Accelerated MD to Characterize Long Time-Scales in Proteins and Estimate the Reorganization Free energy upon Ligand Binding"
    1:30-2: Vijay Pande [ 25 min ] - "Combining Markov State Models with Free Energy Calculations for Allostery"
    2-2:20: Coffee break [ 20 min ]
    2:20-2:50: Tom Woolf [ 25 min ] - "Exchange Protein Activated by cAMP (EPAC): Transitions in Allosteric Binding"
    2:50-3:20:  Christophe Chipot [ 25 min ] - "Calculations of standard binding free energies using adaptive biasing forces"
    3:20-3:40: Coffee break [ 20 min ]
    3:40-4:10: Michel Cuendet  [ 25 min ] - Adiabatic Free Energy Dynamics
    4:10-4:30: Richard Dixon - moderated discussion
    4:30-4:50: Hideaki Fujitani [ 15 min ] - "Molecular dynamics simulations with FUJI force field"
    4:50-5:10: Hironori Kokubo  [ 15 min ] - "Prediction of Protein-Ligand Binding Structures by Generalized-Ensemble Simulation"

Non-speaking attendees (poster presenters indicated)

  • Allen, William (Stony Brook University) Poster
  • Borhani, David (D. E. Shaw)
  • Branson, Kim (Discovery Engine)
  • Brown, Scott (Sunivion).
  • Case, David (Rutgers)
  • Campbell, Arthur (AstraZeneca)
  • Cheng, Alan (Amgen) Poster
  • Chin, Donovan (Novartis)
  • Curuksu, Jeremy (MIT)
  • Deng, Nanjie (Rutgers)
  • Denny, R. Aldrin (Pfizer)
  • Dill, Ken A. (Stony Brook University)
  • Fochtman, Brian (Stony Brook University) Poster
  • Gao, Cen (Eli Lilly)
  • Guilbert, Christophe (UCSF)
  • Hempel, Judith (Duke University)
  • Hidresh, Kumar (IIT, Delhi, India) Poster
  • Huang, Yulin (Stony Brook University) Poster
  • Jiang, Lingling (Stony Brook University) Poster
  • Kato, Mitsunoori (Novartis)
  • Kim, Byungchan (Schrodinger)
  • Kumar, Hirdesh (Indian Institute of Technology) Poster
  • Labute, Paul (CCG)
  • Lamb, Michelle (AstraZeneca)
  • Lawrenz, Morgan (Stanford University) Poster
  • Lin, Teng (Schrödinger)
  • Mahboobi, S. Hanif (Berkeley) Poster
  • McKay, Dan (Novartis)
  • Miller, Matthew (AstraZeneca)
  • Okada, Okimasa (Mitsubishi Tanabe Pharma) Poster
  • Parameswarn, Sreeja (University of New Orleans) Poster
  • Paulino, Margot (UdelaR) Poster
  • Sanders, Jeffrey (Thomas Jefferson University) Poster
  • Shams, Hengameh (Berkeley) Poster
  • Shi, Yue (University of Texas, Austin)
  • Shriram, Purohit (S.E.T. College of Pharmacy, Dharwad, India) Poster
  • Stouch, Terry (Science for Solutions, LLC) Poster
  • Swift, Robert (University of California, San Diego) Poster
  • Tsui, Vickie (Genentech)
  • Wickstrom, Lauren (Rutgers) Poster
  • Wu, Yujie (Schrödinger)
  • Zheng, Zhong (St. Jude Children's Research Hospital) Poster
  • Zunini, Margot Paulino (Universidad de la República, Uruguay) Poster

Restaurants in Boston

Cambridge Restaurants

Directions from Cambridge to Boston

MBTA: Red Line from Kendall to MGH (one stop) takes you to the top of Charles Street, the Liberty Hotel, and the Beacon Hill neighborhood of Boston. In Boston, continuing on the Red Line one additional stop to Park Street is the connection to the Green Line. Inbound one stop on the Green Line is Government Center – a short walk from there to Faneuil Hall. Outbound on the Green Line from Park Street Station will take you to the Back Bay neighborhood – Arlington & Copley Square stations. All of this from Park Street is also very walkable above ground. A quick cab or a 15 minute stroll south of Back Bay (down Clarendon Street is one route) takes you to the South End neighborhood.

Beacon Hill Restaurants

Back Bay Restaurants

South End Restaurants

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