Author: Vincent Voelz

Excited to share work now out in Journal of Chemical Information and Modeling :

Novack, Dylan, Robert M. Raddi, Si Zhang, Matthew F. D. Hurley, and Vincent A. Voelz.Simple Method to Optimize the Spacing and Number of Alchemical Intermediates in Expanded Ensemble Free Energy Calculations. Journal of Chemical Information and Modeling 65, no. 12 (2025): 6089–6101. https://doi.org/10.1021/acs.jcim.5c00704

First, we estimate the thermodynamic length between intermediates using a short expanded-ensemble (EE) simulation, and then use a cubic spline fit to do gradient-based optimization of the spacing.

Using the same approach, we also optimize the number of intermediates used in EE simulations, which sample all intermediates during a simulation by proposing/accepting transitions between ensembles using Monte Carlo. Modeling this Markov process reveals the optimal number of intermediates that minimize the mixing time.

Here’s a result for a toy system of 1D harmonic potentials:

More mixing leads to smaller uncertainties. Sure enough, EE sampling with the optimal number of intermediates (K*=25) gives the lowest uncertainty.

Does it work in realistic systems?  You bet!   Here’s a relative binding free energy calculation where we alchemically transform Ala to Phe using pmx in GROMACS.  Optimized intermediates yield EE simulations that converge faster to accurate estimates.

Want to try it yourself? Check out our freely available Python scripts at https://github.com/vvoelz/pylambdaopt. 

We also note that this approach should also work well for other methods using exchanges between thermodynamic ensembles (REMD or HREX), with some adjustments. It could also improve uncertainties in NEW.  If you are interested, let us know!

–Vincent Voelz

2024 has been quite a busy year, yet somehow I’ve managed to avoid posting anything! Here’s a round-up of some of the many facets of the lab from 2024 (so far):

• January 2024: Chemistry PhD student Starwing Chen joins the Voelz Lab — welcome Starwing!
• February 10–14, 2024: The Biophysical Society Annual Meeting comes to Philadelphia. Five Voelz Lab members attend, four present!
• March 17–20, 2024: Dylan Novack and PI Vincent Voelz give dueling talks (same time, different sessions) at the American Chemical Society Spring Meeting in New Orleans, LA. Dylan’s talk: “Can massively parallel free energy calculations improve in silico affinity maturation of de novo designed miniproteins?” (COMP Drug Design session) Vince’s talk: “Multi-ensemble Markov Model approaches for folding, binding, and design” (COMP invited symposium on Markov State Modeling of Conformational Dynamics in the Wake of Machine Learning)
• May 6, 2024: Robert Raddi gets a Ph.D! His thesis, “A Bayesian Inference/Maximum Entropy Approach for Optimization and Validation of Empirical Molecular Models” is focused on major theoretical advances to our BICePs algorithm and its applications. Congratulations Rob!
• May 23, 2024: Chemistry grad student Julie Nguyen advances to candidacy with a successful defense of her Original Research Proposal “Exploring the Mechanism of Molecular Glues in Modulating CRBN’s Selectivity in CK1α Degradation Using Computational Methods”. Congrats Julie!
• June 11, 2024: Dylan Novack gets a Ph.D.! Their thesis, “Molecular Simulation of Mutation Effects on Protein Folding and Function” focused on Markov model and alchemical free energy approaches made possible though distributed computing on Folding@home.
• July 2024: PI Vincent Voelz is promoted to Full Professor of Chemistry at Temple University.
• August 2024: Starwing Chen presents a poster and flash talk at the 12th Peptoid Summit: “Benchmarking peptoid force fields against solution NMR data”
• September 2024: Temple Bioinformatics Ph.D. student Jason Cargill joins the lab — welcome Jason!
• October 2024: The Annual Voelz Lab Halloween Group Meeting is a unmitigated success.

Happy Halloween from the Voelz Lab!

We have a new paper out that has just been published in the journal Biochemistry, for inclusion in a special issue “Computational Biochemistry”. Check it out:

Improved Estimates of Folding Stabilities and Kinetics with Multiensemble Markov Models. Si Zhang, Yunhui Ge, and Vincent A. Voelz. Biochemistry, Biochemistry 2024, 63, 22, 3045–3056. https://doi.org/10.1021/acs.biochem.4c00573

Learn more from a Folding@home blog post that we wrote explaining our work! https://foldingathome.org/2024/11/16/better-folding-through-biased-simulations/

We wrote a new blog post on Folding@home! To accompany the release of a new preprint, we wrote an explainer about “logP” and our work using distributed simulations to estimate chemical properties for drug discovery. Check it out: https://foldingathome.org/2024/10/03/predicting-drugs-lipophilicity-with-foldinghome/

Expanded ensemble predictions of toluene–water partition coefficients in the SAMPL9 LogP challenge. Steven Goold, Robert M. Raddi, and Vincent A. Voelz. ChemRxiv https://doi.org/10.26434/chemrxiv-2024-rfkkp

On Friday, November 17, Tim Marshall successfully defended his Ph.D Thesis “Comprehensive Markov State Models for Assessing and Improving the Accuracy of Protein Folding Simulations”.

Tim’s work has focused on using MSMs as a platform for evaluating force fields and for examining the ability of molecular simulations to quantitatively predict how mutations affect folding stability, toward the prospect of simulation-based virtual screening for protein design. Tim is still preparing several manuscripts describing this work, so stay tuned for preprints.

Congratulations Tim!

Our new preprint just dropped on ChemRxiv:

Model selection using replica averaging with Bayesian inference of conformational populations.
Raddi RM, Marshall T, Ge Y, Voelz V. https://doi.org/10.26434/chemrxiv-2023-396mm

In this work, we describe and demonstrate with examples how equipping our BICePs algorithm with a replica-averaged forward model makes it a Maximum-Entropy reweighting method with some key advantages:

• It is a post-processing method that does not require restraints implemented inside simulations
• Heuristic estimates of uncertainty are not needed; posterior sampling enables learning uncertainties from the data
• BICePs has improved likelihood models to account for outliers
• The BICePs score can be used for objective model selection
• Automated force field and forward model parameterization can be performed using the BICePs score as an objective function.

I recently spoke about this work at the ACS Fall 2023 symposium “Emerging Techniques to Quantify Biomolecular Conformational Ensembles” symposium. 

Our new paper has been published in the Journal of Chemical Information and Modeling!

Raddi, Robert M., Yunhui Ge, and Vincent A. Voelz. “BICePs v2.0: Software for Ensemble Reweighting Using Bayesian Inference of Conformational Populations.” Journal of Chemical Information and Modeling 63, no. 8 (April 24, 2023): 2370–81. https://doi.org/10.1021/acs.jcim.2c01296.

Congrats to Rob Raddi on this paper and for coding this more user-friendly and extensible Python package: https://github.com/vvoelz/biceps

With five students presenting at BPS, the Voelz Lab made a strong showing at BPS 2023 in San Diego, CA, Feb 18-22! Dylan Novack gave an early-morning (yet still riveting 🙂 Platform Session talk on work simulating FOXO1 and the effects of mutations. Here are the presentations:

An Evaluation of Force Field Accuracy for the Mini-Protein Chignolin using Markov State Models
Tim Marshall, Robert Raddi, Vincent A. Voelz

Model selection using Bayesian inference of conformational populations with replica averaging
Robert M. Raddi, Tim Marshall, Yunhui Ge, and Vincent A. Voelz

ONCOGENIC MUTATIONS IN THE DNA-BINDING DOMAIN OF FOXO1 THAT DISRUPT FOLDING: QUANTITATIVE INSIGHTS FROM EXPERIMENTS AND MOLECULAR SIMULATION.
Dylan Novack
Platform Session Title: Platform: Protein Stability, Folding, and Chaperones

De novo design of beta hairpin peptides with custom installed halogen-bonding groups
Thi Dung Nguyen, Vincent Voelz

Computational fragment screening of dimeric SARS-CoV-2 Main Protease
Rashad Reid Jr., Vincent A. Voelz

Congratulations to Ph.D student Rob Raddi, a 2022 winner of the College of Science and Technology Outstanding Teaching Assistant (TA) at Temple University!    This prestigious college-level award attests to Rob’s excellence in teaching.  Great job and well deserved!