My personal blog, focusing on issues of chemistry and metascience, unified by trying to answer the question "how can we make science better"?

Corin Wagen

“And I took the little scroll from the hand of the angel and ate it.

Bitter Lessons in Chemistry

This post assumes some knowledge of molecular dynamics and forcefields/molecular mechanics.

Are Forcefields Able To Describe Protein Dynamics?

Scientific software can be confusing, particularly when you're doing something that the software isn't primarily intended for.

Running Simple MD Simulations

Much molecular design today can be boiled down to “put the right functional groups in exactly the right places.” In catalysis, proper positioning of functional groups to complement developing charge or engage in other stabilizing non-covalent interactions with the transition state can lead to vast rate accelerations.

Generative Linker Design

Apologies for the long hiatus: we've had some health issues in the family, and startup life has been particularly overwhelming.

The SolidWorks Model of Simulation

In Wednesday’s post, I wrote that “traditional physical organic chemistry is barely practiced today,” which attracted some controversy on X. Here are some responses:

Physical Organic Chemistry: Alive or Dead?

“Like arrows in the hand of a warrior are the children of one's youth.” –Psalm 127:4

Book Review: Hunt, Gather, Parent

An important problem with simulating chemical reactions is that reactions generally take place in solvent, but most simulations are run without solvent molecules.

Machine Learning for Explicit Solvent Molecular Dynamics

The concept of p

 K


 a

is introduced so early in the organic chemistry curriculum that it’s easy to overlook what a remarkable idea it is.

 Briefly, for the non-chemists reading this: p

K

 
 a
 
 is defined as the negative base-10 logarithm of the acidity constant of a given acid H–A:

p

 K


 a

:= -log

 10

([HA]/[A-][H+])

 Unlike pH, which describes the acidity of a bulk solution,

The concept of pKa is introduced so early in the organic chemistry curriculum that it’s easy to overlook what a remarkable idea it is.

pKa and Nonpolar Media

Not Boring recently published a panegyric about Varda, a startup that’s trying to create “space factories making drugs in orbit.” When I first read this description, alarm bells went off in my head—why would anyone try to make drugs in space?

Crystallization in Microgravity

You are a scientist, not a lab monkey. You ought not to view your degree as “six years of hard labor in the chemistry mines.” Always make time to go to interesting seminars, talk with other people about their research, and read the literature. Otherwise, what’s the point of being a scientist? Only one person is really looking out for your best interests: you.

Opinionated Advice for Incoming Graduate Students

Previously, I wrote about various potential future roles for journals. Several of the scenarios I discussed involved journals taking a much bigger role as editors and custodians of science, using their power to shape the way that science is conducted and exerting control over the scientific process.

Editorial Overreach and Scientific Authority

Who was Richard Hamming, and why should you read his book? If you’ve taken computer science courses or messed around enough with

 scipy

, you might recognize his name in a few different places—Hamming error-correction codes, the Hamming window function, the Hamming distance, the Hamming bound, etc. I had heard of some of these concepts, but didn’t know anything concrete about him before I started reading this book.

“They performed his signs among them, and miracles in the land of Ham.” (Psalm 105:27)

Book Review: The Art of Doing Science and Engineering

Much ink has been spilled on whether scientific progress is slowing down or not (e.g.).

Data Are Getting Cheaper

Recently, I’ve been working to assign the relative configuration of some tricky diastereomers, which has led me to do a bit of a deep dive into the world of computational NMR prediction.

Computational NMR Prediction: A Microreview

Note: old versions of this post lacked a discussion of S
 
 N
 
 2. I've added an appendix which remedies this.

In “The Rate-Limiting Span,” I discussed how thinking in terms of the span from ground state to transition state, rather than in terms of elementary steps, can help prevent conceptual errors. Today, I want to illustrate why this is important in the context of a little H/D KIE puzzle.

Note: old versions of this post lacked a discussion of SN2.

Misleading H/D KIE Experiments

Last January, I aimed to read 50 books in 2022. I got through 32, which is at least more than I read in 2021. There’s been a bit of discourse around whether setting numerical reading goals for oneself is worthwhile or counterproductive.

Last January, I aimed to read 50 books in 2022.

Books from 2022

A technique that I’ve seen employed more and more in computational papers over the past few years is to calculate Boltzmann-weighted averages of some property over a conformational ensemble.

Evaluating Error in Boltzmann Weighting

Since my previous “based and red pilled” post seems to have struck a nerve, I figured I should address some common objections people are raising.

Response to Comments on "Against Carbon NMR"

In 2019, ChemistryWorld published a “wish list” of reactions for organic chemistry, describing five hypothetical reactions which were particularly desirable for medicinal chemistry.

Organic Chemistry’s Wish List, Four Years Later

An (in)famous code challenge in computer graphics is to write a complete ray tracer small enough to fit onto a business card.

Business Card Lennard–Jones Simulation

One of the more thought-provoking pieces I read last year was Alex Danco’s post “Why the Canadian Tech Scene Doesn’t Work,” which dissects the structural and institutional factors that make Silicon Valley so much more effective at spawning successful companies than Toronto.

Definite Games, Indefinite Optimism

Who is Peter Thiel? Tyler Cowen calls him one of the most important public intellectuals of our era. Bloomberg called him responsible for the ideology of Silicon Valley “more than any other living Silicon Valley investor or entrepreneur.” Depending on who you ask, he’s either a shadowy plutocratic genius or a visionary forward-thinking genius: but everyone seems to at least agree that he’s a genius.

Book Review: Zero to One

The failure of conventional calculations to handle entropy is well-documented.

Entropy in the Water Dimer

Over the past few weeks, I’ve been transfixed, and saddened, by Eric Gilliam’s three-part series about the history of MIT (my alma mater).

Elegy for the MIT of Yesteryear

This is the second in what will hopefully become a series of blog posts (previously) focusing on the fascinating work of Dan Singleton (professor at Texas A&amp;M).

Singleton Saturday: Nitration of Toluene

The growing accessibility of computational chemistry has, unfortunately, led to a preponderance of papers with bad computations.

Combating Computational Nihilism

Now that our work on screening for generality has finally been published in Nature, I wanted to first share a few personal reflections and then highlight the big conclusions that I gleaned from this project.

Screening for Generality: Reflections

Now that our lab’s site-selective glycosylation has been published, I wanted to share some reflections from the computational portion of the work.

Site-Selective Glycosylation: Reflections

This thesis, from Christian Sailer at Ludwig Maximilian University in Munich, is one of the most exciting studies I’ve read this year.

Plenty of Room at the Bottom

Recently, I wrote about how scientists could stand to learn a lot from the tech industry.

Book Review: Chaos Monkeys

13

C NMR is, generally speaking, a huge waste of time. This isn’t meant to be an attack on carbon NMR as a scientific tool; it’s an excellent technique, and gives structural information that no other methods can. Rather, I take issue with the requirement that the identity of every published compound be verified with a

 13

C NMR spectrum. Very few

 13

C NMR experiments yield unanticipated results.

13C NMR is, generally speaking, a huge waste of time.

Against Carbon NMR

TW: stereotypes about molecular dynamics.

In his fantastic essay “The Two Cultures,” C. P. Snow observed that there was (in 1950s England) a growing divide between the academic cultures of science and the humanities: He reflects on the origins of this phenomenon, which he contends is new to the 20th century, and argues that it ought to be opposed: Snow’s essay is wonderful: his portrait of a vanishing cultural intellectual unity should

TW: stereotypes about molecular dynamics.

The Two Cultures in Atomistic Simulation

Python is an easy language to write, but it’s also very slow.

Optimizing Python

This post is an attempt to capture some thoughts I have about ML models for predicting protein–ligand binding affinity, sequence- and structure-based approaches to protein modeling, and what the interplay between generative models and simulation may look like in the future.

What Achilles Said to the Tortoise About Binding-Affinity Prediction

(Previously: 2022, 2023.)

 #1. Baldassar Castiglione,


 
 The Book of the Courier
 

This book gets cited from time to time as a sort of historical guide to "being cool," since the characters spend some time discussing the idea of

 sprezzatura

, basically grace or effortlessness. More interesting to me was the differences between Renaissance conceptions of virtue, character, &amp;

Books from 2024

Abhishaike Mahajan recently wrote an excellent piece on how generative ML in chemistry is bottlenecked by synthesis (disclaimer: I gave some comments on the piece, so I may be biased).

Robots Won't Solve Organic Synthesis

With apologies to Andrew Marvell. If you haven’t read “To His Coy Mistress”, I fear this won’t make much sense. Had we but funding enough and time, This coyness, founder, were no crime. We would sit down, and think which way To build, and pass our slow run-rate’s day. Thou by the Potomac’s side Shouldst SBIRs find; I by the tide Of El Segundo would complain.

To His Defense-Tech Portco

“A cord of three strands is not easily broken.” —Ecclesiastes 4:12

Composite Methods in Quantum Chemistry

(This is a bit of a departure from my usual chemistry-focused writing.)

What Did The Early Church Think About Fasting?

Last week, I posted a simple Lennard–Jones simulation, written in C++, that models the behavior of liquid Ar in only 1561 characters.

Business Card Lennard–Jones Simulation, Explained

Talent, by Tyler Cowen and Daniel Gross, is a book about talent selection—in other words, a book about hiring.

Book Review: Talent

Since the ostensible purpose of organic methodology is to develop reactions that are useful in the real world, the utility of a method is in large part dictated by the accessibility of the starting materials.

How Common Are Different Functional Groups?

(with apologies to Maimonides and Nozick)

Screening on only one substrate before assessing the substrate scope. This is the “ordinary means” in methods development. Screening on one substrate, but choosing a substrate that worked poorly in a previous study (e.g.). This can be thought of as serial multi-substrate screening, where each substrate is a separate project, but the body of work achieves greater generality over time.

(with apologies to Maimonides and Nozick)

Seven Degrees of Screening for Generality

In our recently published work on screening for generality, we selected our panel of model substrates in part using cheminformatic techniques.

Plotting Chemical Space with UMAP and Molecular Fingerprints

In the course of preparing a literature meeting on post-Hartree–Fock computational methods last year, I found myself wishing that there was a quick and simple way to illustrate the relative error of different approximations on some familiar model reactions, like a "report card" for different levels of theory.

Computational Report Cards

As an undergraduate student in the sciences at MIT, contempt for management consulting was commonplace.

Consulting as Private-Sector Graduate School

I started this blog one year ago today, with a post on site-selective glycosylation.

A Year In The Blog

Quantum computing gets a lot of attention these days. In this post, I want to examine the application of quantum computing to quantum chemistry, with a focus on determining whether there are any business-viable applications today.

Quantum computing gets a lot of attention these days.

Quantum Computing for Quantum Chemistry: Short-Term Pessimism

ICYMI: Ari and I announced our new company, Rowan! We wrote an article about what we're hoping to build, which you can read here. Also, this blog is now listed on The Rogue Scholar, meaning that posts have DOIs and can be easily cited.

EDA Scares Me

A few days ago, I wrote about kinetic isotope effects (KIEs), probably my favorite way to study the mechanism of organic reactions.

What Happened to IRMS?

In many applications, including cheminformatics, it’s common to have datasets that have too many dimensions to analyze conveniently.

Dimensionality Reduction in Cheminformatics

While scientific companies frequently publish their research in academic journals, it seems broadly true that publication is not incentivized for companies the same way it is for academic groups.

Industry Research Seems Underrated

Every year, our group participates in a “Paper of the Year” competition, where we each nominate five papers and then duke it out in a multi-hour debate.

2022 Paper(s) of the Year

Modeling ion-pair association/dissociation is an incredibly complex problem, and one that's often beyond the scope of conventional DFT-based techniques.

Introducing quick_fuoss

In 2007, John Van Drie wrote a perspective on what the next two decades of progress in computer-assisted drug design (CADD) might entail.

Democratizing Computer-Assisted Drug Design: How Are We Doing?

Organic chemists often think in terms of potential energy surfaces, especially when plotting the results of a computational study.

Potential Energy Surfaces in Python

—Richard Hamming What’s the difference between science and engineering? Five years ago, I would have said something along the lines of “engineers study known unknowns, scientists study unknown unknowns” (with apologies to Donald Rumsfeld), or made a distinction between expanding the frontiers of knowledge (science) and settling already-explored territory (engineering). These thoughts seem broadly consistent with what others think.

In science, if you know what you are doing, you should not be doing it.

Science and Engineering

I've been playing around with generating non-equilibrium conformations by molecular dynamics recently, and I've been thinking about how to best parse the outputs of a dynamics simulation.

Choosing Maximally Dissimilar Molecules

(Previously: 2022)

 #1. Tony Fadell,


 
 Build
 


 #2. Giff Constable,


 
 Talking To Humans
 


 #3. Ben Horowitz,


 
 The Hard Thing About Doing Hard Things
 


 #4. Dale Carnegie,


 
 How To Win Friends And Influence People
 

Sounds Machiavellian, but actually quite wholesome: a “dad book,” as my friend

Books for 2023

I took a pistol course in undergrad, and while I was a poor marksman I enjoyed the experience.

Book Review: Working Backwards

Pure mathematics has all sorts of unexpected connections to other fields, and chemistry is no exception.

Molecular Symmetry Analysis Made Easy

The Pauling model for enzymatic catalysis states that enzymes are “antibodies for the transition state”—in other words, they preferentially bind to the transition state of a given reaction, rather than the reactants or products.

Transition States Are Polarizable

Eric Gilliam, whose work on the history of MIT I highlighted before, has a nice piece looking at Irving Langmuir’s time at the General Electric Research Laboratory and how applied science can lead to advances in basic research.

Gilliam and Girard on Scientific Innovation

One of the most distinctive parts of science, relative to other fields, is the practice of communicating findings through peer-reviewed journal publications.

Do We Still Need Journals?

For almost all Hartree–Fock-based computational methods, including density-functional theory, the rate-limiting step is calculating electron–electron repulsion.

The Importance of Integral Screening

While looking over papers from the past year, one theme in particular stood out to me: meta-optimization, or optimizing how we optimize things.

Who Will Optimize The Optimizers?

Today I want to engage in some shameless self-promotion and highlight how cctk, an open-source Python package that I develop and maintain with Eugene Kwan, can make conformational searching easy.

Low-Code Conformational Searching

While IR spectroscopy is still taught in introductory organic chemistry classes, it has been almost completely replaced by NMR spectroscopy and mass spectrometry for routine structural assignments.

The Apotheosis of 2D Infrared Spectroscopy

One common misconception in mechanistic organic chemistry is that reactions are accelerated by speeding up the rate-determining step.

The Rate-Determining Span

In my experience, most computational chemists only know a handful of basic Bash commands, which is a shame because Bash is incredibly powerful.

Four Handy Bash One-Liners

TW: sarcasm.

Today, most research is done by academic labs funded mainly by the government. Many articles have been written on the shortcomings with academic research: Sam Rodriques recently had a nice post about how academia is ultimately an educational institution, and how this limits the quality of academic research. (It’s worth a read;

For-Profit Micro Focused Research Organizations: A Proposal

I did not enjoy John Mark Comer’s book The Ruthless Elimination of Hurry.

The Ruthless Elimination of Mottes

Spoilers below for Ursula Le Guin’s short story “The Ones Who Walk Away From Omelas.” If you haven’t read it, it’s short—go and do so now!

Omelas, Hirschman, Altom: On Healing Academia

I frequently wonder what the error bars on my life choices are.

Tech As Control Group For Science

(in the spirit of Dale Carnegie and post-rat etiquette guides)

Networking, For Skeptics

It’s a truth well-established that interdisciplinary research is good, and we all should be doing more of it (e.g.

Domain Arbitrage

This is the first in what will hopefully become a series of blog posts focusing on the fascinating work of Dan Singleton (professor at Texas A&amp;M).

Singleton Saturday: Dynamics at the Border Between General- and Specific-Acid Catalysis

For many organic chemists, it’s hard to grasp the vast difference between various “fast” units of time.

Timescales

In this post, I’m trying something new and embedding calculations on Rowan alongside the text.

Looking Back on the Norbornyl Cation

I’ve been pretty critical of peer review in the past, arguing that it doesn’t accomplish much, contributes to status quo bias, etc.

Peer Review, Imperfect Feedback

This Easter week, I’ve been thinking about why new ventures are so important.

Why New Ventures Are So Important

In scientific computation, where I principally reside these days, there’s a cultural and philosophical divide between physics-based and machine-learning-based approaches.

The Fundamental Wisdom of the Middle Way

“You dropped a hundred and fifty grand on a f***** education you coulda' got for a dollar fifty in late charges at the public library.” —Good Will Hunting

Teach Yourself Quantum Chemistry (For Fun And Profit)

Recently, Kelsey Piper shared that o3 (at time of writing, one of the latest reasoning models from OpenAI) could guess where outdoor images were taken with almost perfect accuracy.

How Does o3 Guess Latitude From Photos?

Michael Nielsen and Kanjun Qiu recently published a massive essay entitled “A Vision of Metascience: An Engine of Improvement for the Social Processes of Science.” Metascience, the central topic of the essay, is science about science.

Structural Diversity in Science

If you are a scientist, odds are you should be reading the literature more.

You Should Read The Literature More

I first encountered organic chemistry on Wikipedia, my freshman year of high school.

A Farewell To Lab

I’m writing my dissertation right now, and as a result I’m going back through a lot of old slides and references to fill in details that I left out for publication.

Isotope Effects in Aldehyde Protonation

When thinking about science, I find it helpful to divide computations into two categories: models and oracles.