Director - Molecular Dynamics

At Lilly, the work is demanding because patients are waiting. We unite caring with discovery to help make life better for people around the world, knowing that every decision, every detail, and every day matters. Headquartered in Indianapolis, Indiana, our over 50,000 employees around the globe take on complex challenges to discover and deliver life-changing medicines, strengthen how health is understood and managed, and support the communities we serve.

This is hard, urgent, selfless work—but it’s work worth doing. If you’re driven by purpose and ready to bring your best to work that truly matters for patients, we invite you to join us.

Build the mechanistic model that tells our chemists what to make next

Lilly's RNA Therapeutics organization is hiring a computational biophysicist in South San Francisco. The work is to establish, at atomic resolution, how chemical modifications change the way an siRNA guide strand loads into Argonaute 2, and to turn that understanding into design rules our medicinal chemists can act on.

For over 150 years we have worked to discover medicines that make life better. Those discoveries start in Lilly Research Laboratories, where our scientists work on new medicines for the world’s hardest health problems.

Lilly has operated in South San Francisco since 2019 and runs two Bay Area sites. Computational scientists here work alongside oligonucleotide chemists, structural biologists and automated laboratories. The site gives you a small-company working environment with the resources of a global research organization, in one of the largest life science clusters in the world.

About the role

How chemical modification governs guide-strand loading into Ago2, and the catalytic activity of the resulting complex, is still poorly understood. Seed-pairing nucleation, passenger-strand release and catalytic slicing together set the potency, selectivity and duration of effect of an RNA medicine, and none of them can currently be predicted from a modification pattern.

You will build molecular dynamics and free-energy models of Ago2 guide-strand complexes from internal cryo-EM, crystallographic and biophysical data, and use them to predict how modification patterns affect loading, passenger-strand release and catalytic efficiency. Those predictions become specific design proposals that get synthesized and tested. The models inform chemistry decisions across siRNA programs in neurodegeneration, pain, cardiometabolic disease and immunology, where no single modification pattern will serve every tissue.

You

will work hands-on as an individual contributor, with the expectation that in the near term you also lead a team of senior computational scientists while staying close to the science. The work is run in close and continuous contact with medicinal chemistry, structural biology and biochemistry. Structural, biophysical and functional data are generated internally, and you will use them to ground and test models that shape how we modify oligonucleotides across the portfolio.

Key responsibilities

• Model how 2'-F, 2'-OMe, phosphorothioate, LNA/cEt, stereo defined linkages, thermally destabilizing modifications and conjugation chemistry affect duplex thermodynamics, Ago2 binding and RISC catalytic efficiency.
• Run all-atom, enhanced-sampling (meta dynamics, umbrella sampling, replica exchange) and coarse-grained simulations of siRNA duplexes, Ago2 guide-strand complexes and RISC loading intermediates, building simulation-ready models from cryo-EM, crystallographic, HDX-MS and SAXS data.
• Quantify the energetics and conformational dynamics of guide-strand loading, seed-pairing nucleation, passenger-strand ejection, RISC stability and target cleavage.
• Model the structural basis of seed-mediated…