Director - Molecular Dynamics

Lilly•South San Francisco, CA

3d•$168,000 - $264,000•Onsite

About The Position

Lilly's RNA Therapeutics organization is hiring a computational biophysicist to establish, at atomic resolution, how chemical modifications affect siRNA guide-strand loading into Argonaute 2 (Ago2), and to translate mechanistic understanding into actionable design rules for medicinal chemists. The role addresses how chemical modification governs guide-strand loading and the catalytic activity of the resulting complex, including seed-pairing nucleation, passenger-strand release, and catalytic slicing—processes that influence an RNA medicine's potency, selectivity, and duration of effect. The Director will build molecular dynamics and free-energy models of Ago2 guide-strand complexes using internal cryo-EM, crystallographic, and biophysical data. Models will be used to predict how modification patterns affect loading, passenger-strand release, and catalytic efficiency, then inform design proposals that are synthesized and tested. The work supports siRNA programs in neurodegeneration, pain, cardiometabolic disease, and immunology, recognizing that different tissues may require different modification patterns. This is a hands-on individual-contributor role, with an expectation of leading a team of senior computational scientists in the near term while remaining closely engaged in the science. The position works continuously with medicinal chemistry, structural biology, and biochemistry, using internally generated structural, biophysical, and functional data to ground and test models that guide oligonucleotide modification across the portfolio. The position is based on site in South San Francisco, California, with regular collaboration with Lilly colleagues in Boston, Indianapolis, and San Diego.

Requirements

PhD in biophysics, computational chemistry, chemical physics, structural biology, or a related STEM field.
Five or more years of relevant postdoctoral or industry experience running and analyzing molecular dynamics simulations of protein–nucleic acid systems.
Experience with MD engines such as AMBER, GROMACS, NAMD, OpenMM, CHARMM, or equivalent.
Experience with free-energy methods including FEP, TI, umbrella sampling, or metadynamics.

Nice To Haves

Knowledge of modern RNA and DNA force fields and parameterization of modified nucleotides or non-canonical backbones.
Knowledge of Argonaute biology, RNAi mechanisms, or siRNA therapeutic chemistry.
Experience building simulation-ready models from cryo-EM, crystallographic, or predicted structures, including flexible regions and missing loops.
A track record of prospective computational predictions that were experimentally tested and informed design decisions.
Industry experience on an RNAi or oligonucleotide program, working directly with medicinal chemistry.
Python skills and experience building reproducible analysis pipelines.

Responsibilities

Model how 2'-F, 2'-OMe, phosphorothioate, LNA/cEt, stereodefined linkages, thermally destabilizing modifications, and conjugation chemistry affect duplex thermodynamics, Ago2 binding, and RISC catalytic efficiency.
Run all-atom, enhanced-sampling (metadynamics, umbrella sampling, replica exchange), and coarse-grained simulations of siRNA duplexes, Ago2 guide-strand complexes, and RISC loading intermediates.
Build 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 off-target engagement and how destabilizing chemistry at the seed region affects the balance between on-target potency and off-target activity.
Translate simulation output into testable structure-activity hypotheses and work directly with medicinal chemists to prioritize subsequent modification patterns.
Test predictions against biophysical (ITC, SPR, DSC) and functional (knockdown, RISC loading) data, and revise models when predictions are not borne out.
Build and maintain simulation pipelines and force-field parameters for non-natural nucleotides, including free-energy workflows such as FEP/TI, umbrella sampling, and metadynamics.
Present mechanistic findings and chemistry recommendations to chemists, biologists, and RNA Therapeutics leadership.
Publish, patent, and present findings externally.
Lead a team of senior computational scientists in the near term while continuing hands-on scientific work.

Benefits

Company bonus for full-time equivalent employees, depending in part on company and individual performance.
Eligibility to participate in a company-sponsored 401(k).
Pension.
Vacation benefits.
Eligibility for medical, dental, vision, and prescription drug benefits.
Flexible benefits, such as healthcare and/or dependent day care flexible spending accounts.
Life insurance and death benefits.
Certain time off and leave of absence benefits.
Well-being benefits, such as an employee assistance program, fitness benefits, and employee clubs and activities.
Employee resource groups open to all employees.