News & Events

Rajat Pal final PhD thesis defense!

posted Nov 9, 2019, 8:25 AM by Emilio Gallicchio

Congratulations to Rajat who successfully defended his Ph.D. thesis "Advanced Computational Methodologies to Study Binding Free Energies of Biomolecular Complexes" on Thursday 11/7/2019. 

  • 3 first-author publications (so far)
  • 3 contributing publications
  • thesis dissertation

Way to go Dr. Pal!

Talk at the Structure-Based Drug Discovery Conference (SBDD2019) on Free Energy-Based Virtual Screening

posted Oct 1, 2019, 3:48 AM by Emilio Gallicchio

The talk, titled "Theory, Methods, and Software for Free Energy-Based Virtual Screening," was delivered on September 23, 2019 at the SBDD 2019 conference. It presents our recent efforts to develop binding free energy methods and software applicable to virtual drug screening.

Free Energy-Based Virtual Screening

Manuscript on Order/Disorder Transitions in Alchemical Binding Free Energy Calculations

posted Jul 15, 2019, 3:39 PM by Emilio Gallicchio   [ updated Jul 17, 2019, 5:39 AM ]

We completed the first draft of a work in which we discuss order/disorder phase transitions in alchemical calculations. In the manuscript, deposited in arXiv, we show that order/disorder transitions cause sampling bottlenecks and slow down or even prevent convergence of binding free energies. We then use our analytical model of alchemical binding and the formalism developed by John Straub et al to model conventional phase transitions, to design novel perturbation potentials and soft-core functions to avoid alchemical order/disorder transitions. 


In alchemical binding, the interactions between a ligand and a receptor are slowly created anew. When ligand and receptor are uncoupled, they can freely translate and rotate with respect to each other--that is if they are allowed to; sometimes restraining potentials are applied to prevent rotations. Intramolecular degrees of freedom (dihedral angles, etc.) can also show greater fluctuations when ligand and receptor are not interacting. In statistical thermodynamics, we say that the uncoupled ensemble of the protein-ligand complex has high conformational entropy. It's a disordered state of the complex. In contrast, the coupled ensemble is an ordered state with low entropy, because specific interactions between ligand and receptor (hydrogen bonds, etc.) can only occur in very specific poses and orientations of the ligand relative to the receptor. The bottom line is that ligand and receptor have to lose entropy in order to reach the bound state. This is possible only if the entropic loss is matched by a corresponding lowering of the energy from the net formation of protein-ligand interactions.
There you go: lose entropy, lose energy, snap! Protein and ligand bind each other. But not so fast (pun intended). it's not so easy to lose entropy. Losing entropy means finding a very unlikely state that happens to also have low energy. It's like throwing a golf ball at random in a golf course hoping that it falls into one of the 18 holes. The process of entropy loss in molecular binding is not unlike the process of crystallization and protein folding. In all of these cases, the molecular system has to go through a lengthy search process to find that rare configuration that happens to be near an energy minimum. This paper is about speeding up the search by playing tricks with potential functions and such. 
And there is also something called microscopic reversibility: an equilibrium process that speeds up the reaction in one direction must speed up the reverse reaction by the same amount. These tricks do indeed speed up the rates of unbinding as well ...

The work has been made possible by the National Science Foundation and XSEDE

Talk at the Spring ACS Meeting on Overcoming Order/Disorder Transitions during Alchemical Transformations

posted Apr 3, 2019, 10:39 AM by Emilio Gallicchio

The talk (see slides below) is a contribution to an exciting symposium on conformational sampling organized by Pratyush Tiwari, Ao Ma, and Wei Yang. It presents research that shows that the convergence of protein-ligand alchemical binding free energy calculations is often hampered by order/disorder transitions and that these can be circumvented by simulating ensembles other than the canonical ensemble.

Excellent poster of Rajat Pal at the Spring ACS meeting

posted Apr 3, 2019, 9:55 AM by Emilio Gallicchio

Rajat illustrating his poster "Non-equilibrium Alchemical Molecular Dynamics Formulations to Study Molecular Binding"

Introducing Alchemical Models to Students at Pace University

posted Apr 3, 2019, 9:49 AM by Emilio Gallicchio

It was great to visit Prof. Nanjie Deng at Pace University. I enjoyed giving a guest lecture to his students introducing alchemical simulations. The slides of my lecture are below:

New Paper on an Analytic Model of Alchemical Molecular Binding

posted Nov 12, 2018, 9:45 PM by Emilio Gallicchio

Our work on an analytic model of alchemical molecular binding has been published in the Journal of Chemical Theory and Computation!

The main idea of the model is that the binding free energy, the alchemical free energy profile, the probability distributions of the perturbation energy, and pretty much any thermodynamic observable of the alchemical binding equilibrium can be derived from a single quantity: p0(u), the probability density of the receptor-ligand interaction energy in the ensemble in which they are not interacting. (The concept of asking about the probability of something when that something is not active is weird, but maybe not so weird if you ever thought about alchemical calculations.) Anyway, we set out to develop an analytic model for p0(u) and derived everything else from that. The key here is "analytic", that is a mathematical expression that you can write down on a piece of paper so that all of the derived quantities (binding free energy, free energy profile, perturbation energy distributions, etc.) are all analytic as well. You can then vary the parameters of the model to discover how the properties of the system affect the alchemical equilibrium.

What can you do with that? Well, we are still discovering new ways, but we have already shown that the parameters of the analytic model fit to the data from molecular simulations yield a wealth of information such as the size and flexibility of the receptor binding pocket and the presence of multiple binding modes. We believe that these parameters will be useful as classifiers of molecular complexes. And we are already using the model to optimize the settings of alchemical calculations, such as the lambda schedule. 

Amédée Des Georges talk on cryoEM-based investigation of protein conformational changes

posted Oct 9, 2018, 8:01 AM by Emilio Gallicchio

Amédée Des Georges (City College & ASRC of CUNY) is visiting the Department of Chemistry at Brooklyn College to talk about the latest cryo-EM and image reconstruction technologies to study functional conformational transitions of protein complexes.

Amédée Des Georges

Insights into Ryanodine Receptor Ligand Binding and Gating Using Cryo-EM and Geometric Machine Learning

Wednesday, October 10th, 2018

2:20 pm, Room 133NE Ingersoll Hall

Sci-Mix at Fall ACS Meeting in Boston

posted Aug 27, 2018, 2:57 PM by Emilio Gallicchio   [ updated Aug 27, 2018, 3:09 PM by Rajat Kumar Pal ]

Rajat Pal explains his recent work on the D3 Dopamine Receptor at the Fall ACS Meeting in Boston. His poster has been selected for the Sci-Mix event. Congratulations!


Poster on Analytic Model for Molecular Binding at the Fall ACS Meeting in Boston

posted Aug 27, 2018, 2:48 PM by Emilio Gallicchio

Emilio Gallicchio presented a model to extract physical parameters from alchemical binding free energy profiles at the COMP poster session at the Fall ACS Meeting in Boston.

1-10 of 58