Boston 2018

Description

The 2018 workshop titled 2018 Workshop on Free Energy Methods, Kinetics and Markov State Models in Drug Design brought together scientists from academia and industry to explore how advanced computational techniques—particularly alchemical free-energy methods, kinetic modelling, and Markov State Models (MSMs)—can influence drug-design workflows. The meeting was held May 14-18th, 2018. The sessions covered the state of the art in binding-free-energy calculations, force-field parameterisation, and the emerging importance of modelling ligand kinetics (on- and off-rates) in addition to binding affinity; they emphasized integrating these methods into real-world medicinal-chemistry pipelines, while also addressing challenges such as sampling bottlenecks, reproducibility, and community benchmarking.

Organization Committee

Keynote Speaker: Mark Murcko

Institution: Drug Hunter, Board member of many Biotechs, Pharma Exec
Title: “NA”

Schedule

May 14th, 2018 (Day 1)

Time (PM EST)	Speaker	Title
6:00	Woody Sherman	Welcome with Food and Drinks
7:00	Darrin York	Toward a GPU-Accelerated Free Energy Pipeline for High-throughput Lead Optimization
7:15	Stefan Doerr	ACEMD-ai: Ab-initio machine learning calculations of small molecules quantum energies and forces
7:30	Sergio Decherchi	Kinetics of Protein-Ligand Unbinding Via Smoothed Potential Molecular Dynamics Simulations
7:45	RECEPTION AND DRINKS

May 15th, 2018 (Day 2)

Time (EST)	Speaker	Title
8:30		Morning Reception
Session Chair: Woody Sherman		Free Energy Simulations in the Real World
9:00	Mike Schnieders	Welcome and Opening Remarks
9:10	Mark Murcko (Keynote)	NA
9:40	Christina Schindler	Large scale free energy calculations in drug discovery at Merck KGaA
10:10	RREAK
10:30	Guanglei Cui	Assessing the Performance of Relative Affinity Predictions: from Null Model to Null Systems
11:00	Aysegyl Ozen	Lessons from retrospective FEP on NAMPT
11:30	Katharina Meier	Binding Free Energy Calculations in Active Drug Discovery Projects
12:00	LUNCH
**Session Chair: Jay Ponder		Increasing the Domain of Applicability of Free Energy Simulations: Salt, pH, Force Fields and Proteins
1:30	Gregory A. Ross	Biomolecular simulations under realistic macroscopic salt conditions
1:45	Marie Laury	Calculating host-guest binding free energies via the AMOEBA polarizable force field
2:00	Jana Shen	How to incorporate pH in protein-ligand binding free energy calculations
2:30	Christopher Bayly	SMIRNOFF and the Open Force Field Consortium
3:00	RREAK
3:15	Matteo Aldeghi	Predictions of ligand binding affinity changes upon protein mutation using non-equilibrium free energy calculations
3:45	Charlie Brooks	Probing Epistasis in Protein Design with High-Throughput Free Energy Methods
4:15	RREAK
4:30	Pratyush Tiwary	Designing dynamical maps for biomolecules with statistical mechanics & predictive artificial intelligence
5:00	Thomas Simonson	Accurate PDZ:peptide binding free energies with additive and polarizable free energy simulations
5:30	POSTER SESSION

Poster Session 1

Presenter	Affiliation	Title
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	Schrödinger Inc.	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.	AMOEBA Binding Calculations for SAMPL Host-Guest System
Stefan Doerr	Acellera	ACEMD-ai: Ab-initio machine learning calculations of small molecules quantum energies and force

May 16th, 2018 (Day 3)

Time (EST)	Speaker	Title
8:30		Morning Reception
Session Chair: John Chodera		Beyond Binding Affinity: Simulations for Membrane Permeability, Polymorphs, Hydration and Pose Prediction
9:00	Chris Chipot	Influence of the membrane composition on its permeability to drugs
9:30	Michael Shirts	Free energies of crystal polymorphs: what sorts of approximations can we get away with?
10:00	Dave Huggins	Estimating Atomic Contributions to Small-Molecule Hydration and Protein-Ligand Binding Using Free-Energy Perturbation
10:30	RREAK
10:50	Lucie Delemotte	GMM with cross-validation allows a robust estimation of free energies: application to the Calmodulin conformational ensemble
11:20	Germano Heinzelmann	APRprotein: Attach-pull-release calculations applied to bromodomains as a pose refinement and ligand ranking tool
11:50	LUNCH
**Session Chair: Mike Schnieders		Advances in Theory and Software for Free Energy Simulations
1:20	Sathesh Bhat	Solving Real World Drug Discovery Problems with Free Energy Calculations
1:50	Jean-Philip Piquemal	Accelerating free energy evaluation with Tinker-HP
2:20	Woody Sherman	Overcoming Discovery Bottlenecks on Challenging Targets using Molecular Simulations in an Integrated Biology/Chemistry/Physics Company
2:50	RREAK
3:10	Léa El Khoury	Absolute Binding Free Energy Predictions for Heat Shock Protein 90 (HSP90) Complexes
3:40	Israel Cabeza de Vaca	Estimating absolute binding free energies through Monte Carlo simulations
4:10	RREAK
4:30	David Ryan Koes	Docking Deeply: Molecular Docking with Deep Learning Potentials
5:00	JC Gumbart	Conformational dynamics of HBV capsid proteins in free and drug-bound states
5:30	Lingle Wang	Pushing the Boundaries of Free Energy Calculations
6:00	DISCUSSION	Grand Challenges in Free Energy Simulations

May 17th, 2018 (Day 4)

Time (EST)	Speaker	Title
8:30		Morning Reception
9:00	John Chodera	Welcome
9:15	Greg Bowman	Identifying and targeting excited states
9:45	Simon Olsson	Models of molecular kinetics driven by simulation and experiment
10:00	Purushottam Dixit	A maximum entropy based variational approach to manipulate Markov state models
10:15	RREAK
10:45	Vio Buchete	Kinetic conformational networks for folding and protein-protein interactions: From amyloid peptides to kinase signaling
11:15	Sonya Hanson	What makes a kinase promiscuous for inhibitors?
11:30	Bryn Taylor	Structural basis for ligand modulation of CCR2 activation pathways using Markov state models
11:45	Benoit Roux	Predicting the Conformational Variability of Abl tyrosine kinase using Molecular Dynamics Simulations and Markov State Models.
12:15	LUNCH
2:00	Dan Zuckerman	Simple trajectory physics for path sampling and improving Markov models
2:30	Justin Porter	Exposons detect functionally-relevant conformational changes
3:00	Chia-En Chang	Modeling ligand-protein binding kinetics using molecular simulations
3:30	Vince Voelz	Markov State Model approaches to elucidate ligand binding mechanisms
4:00	POSTER SESSION

Poster Session 2

Presenter	Affiliation	Title
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 Inc.	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
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	Schrodinger Inc	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

May 18th, 2018 (Day 5)

Time (EST)	Speaker	Title
8:30		Morning Reception
9:00	Frank Noe	Deep learning for molecular kinetics
9:30	Maxwell Zimmerman	Choice of adaptive sampling strategy impacts state discovery, transition probabilities, and the apparent mechanism of conformational changes
9:45	Antonia Mey	The role of fast motion in relation to catalysis in Cyclophilin variants
10:00	Jordi Juarez-Jimenez	Computational and experimental approach for the detailed characterization of minor states in proteins: application to Cyclophilins loop dynamics
10:15	RREAK
10:45	Bettina Keller	Girsanov reweighting for metadynamics simulations
11:15	Fabian Paul	Estimating transitions rates of ultimate rare events using the transition-based reweighting analysis method
11:30	Cecilia Clementi	Incorporating experimental data in long-timescales macromolecular simulations
12:00	LUNCH
1:30	Rebecca Wade	Computationally efficient approaches to estimate drug-target binding kinetic parameters
2:00	Zhifeng Jing	Many-body effect determines the selectivity of Ca vs Mg in proteins
2:15	Muneeb Sultan	Using Markov state models to accelerate free-energy simulations
2:30	Gianni de Fabritiis	Simulations meet machine learning in structural biology

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