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Alex MacKerell

@alexmackerell.bsky.social

Computational chemistry and biophysics. Empirical force fields, CADD, RNA, carbohydrates, and methods developments including SILCS (site identification by ligand competitive saturation, See SilcsBio LLC) and enhanced-sampling GCMC. And I surf....

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Elizabeth Warren@warren.senate.gov · 21h ago

If Congress doesn’t act, Social Security benefits are on track be cut in 2032. Not on my watch. We must protect Social Security by lifting the cap so that those with the highest incomes pay the same share as everyone else.

“Just take the cap off” Elizabeth Warren on removing the Social Security tax cap to make the highest earners pay their fair share.
Alex MacKerell@alexmackerell.bsky.social · 3w ago

Check out our paper on identification of ligand binding sites starting from apo RNA using enhanced sampling with the Drude polarizable force field and the SILCS technology in conjunction with RNA specific collective variables and scoring functions. pubs.acs.org/jctcce/artic...

Integrating Enhanced Molecular Sampling, RNA-Specific Scoring Functions, and SILCS Technology for Small-Molecule Targeting of RNA

Abstract. Increasing knowledge of the wide range of biological functions of ribonucleic acids (RNAs) has made them a critical target in drug development. A

pubs.acs.org

Alex MacKerell@alexmackerell.bsky.social · 5mo ago

Nice. That reminds of a photo I took of the Boston skyline from Marblehead MA back around 1990. It was one of those chance moments when the sky, land, and sea all came together. I was using Ektachrome 400 ASA so the image is rather grainy.

Photo of the Boston skyline taken from Marblehead, MA. There is a wave breaking in the foreground.
Tyler K. Stroud@stroudarian.bsky.social · 5mo ago

What you see in the Sun, is the Chicago skyline from the Indiana Dunes beach, across Lake Michigan. You can see it from 50 miles of distance due to a form of superior mirage, because the skyline is seen above where it's actually located. [📷 wesskywalker]

Alex MacKerell@alexmackerell.bsky.social · 6mo ago

Applying SILCS to identify a novel binding site, develop pharmacophores for in silico screening and rank compounds we helped identify HIF inhibitors that are active against a variety of tumors.

Journal of Experimental Medicine@jem.org · 6mo ago

Salman et al. develop the first dual HIF-1/2 inhibitors that bind to the most highly conserved domains of both proteins, show activity against a range of cancers, are orally bioavailable, & markedly improve responses to immune checkpoint blockade in mouse tumor models. rupress.org/jem/article/...

Alex MacKerell@alexmackerell.bsky.social · 7mo ago

Those timings include the presence of lone pairs and anisotropic polarizability on selected H-bond acceptors, LJ terms on selected Drudes and other features that maximize the accuracy of the CHARMM-Drude model. And it can be used for FEP, metadynamics etc. using CHARMM or OpenMM/PLUMED.

Marcelo D. Polêto@mdpoleto.bsky.social · 7mo ago

For reference, CHARMM-Drude is 3-4x slower than C36 due to the 1fs integration time step and the presence of Drude particles in every heavy atom (almost duplicating the system size). Still, 6x slower is a lot!

@benoitroux.bsky.social · 8mo ago

We developed a simple theory and showed that Random Acceleration Molecular Dynamics (RAMD) is consistent with a Smoluchowski equation with an effective temperature and diffusion coefficient that depend quadratically on the magnitude of the random force. pubs.aip.org/aip/jcp/arti...

A theoretical framework for random acceleration molecular dynamics simulations

The dissociation of a ligand bound to a receptor is a rare event occurring on a timescale that is far longer than can be afforded by standard simulation methodo

pubs.aip.org

Alex MacKerell@alexmackerell.bsky.social · last yr.

Take a look. The perspective includes examples of how MD simulations and the SILCS technology can be used to facilitate antibody-drug conjugate (ADC) development including regions of the mAb that have potential interactions with the drug warhead.

Images of the Fab and Fc regions of the NIST monoclonal antibody showing the site identification by ligand competitive saturation (SILCS) FragMaps along with where the drug conjugate warhead can bind as predicted by the SILCS and how those regions correspond with residues predicted by MD simulations to interact with the warhead.
Nature Chemical Biology@natchembio.nature.com · last yr.

A new Perspective by Anastasia Croitoru, Asuka Orr, and @alexmackerell.bsky.social discusses how computational methods can be used to facilitate the early-stage development and optimization of antibody-drug conjugates www.nature.com/articles/s41...

Alex MacKerell@alexmackerell.bsky.social · last yr.

Nice to get a JCIM cover! Check out the SILCS-based method for dissociation pathway identification, 10.1021/acs.jcim.4c01814, and the SILCS-Kinetics physics/ML method for rapid estimation (really fast...) of small molecule koff values was just accepted in JCTC. @silcsbio

Representative images on a journal cover of the different types of molecular movement pathways.
Alex MacKerell@alexmackerell.bsky.social · 2y ago

For all the CGenFF fans out there, we've undertaken a significant expansion of the training set and extended the coverage to 4-membered rings. pubs.acs.org/doi/10.1021/... Access CGenFF at cgenff.com

Increasing the Accuracy and Robustness of the CHARMM General Force Field with an Expanded Training Set

Small molecule empirical force fields (FFs), including the CHARMM General Force Field (CGenFF), are designed to have wide coverage of organic molecules and to rapidly assign parameters to molecules no...

pubs.acs.org