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, 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, 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 off-target engagement, and how destabilizing chemistry at the seed region alters the balance between on-target potency and off-target activity. Convert simulation output into testable structure-activity hypotheses, and work directly with medicinal chemists to prioritize the next round of modification patterns. Test predictions against biophysical (ITC, SPR, DSC) and functional (knockdown, RISC loading) data, and revise the models when they are wrong. Build and maintain simulation pipelines and force-field parameters for non-natural nucleotides, including free-energy workflows (FEP/TI, umbrella sampling, metadynamics). Present mechanistic findings and chemistry recommendations to chemists, biologists and RNA Therapeutics leadership, and publish, patent and present externally. Basic qualifications PhD in biophysics, computational chemistry, chemical physics, structural biology or a related STEM field. Five+ years of relevant experience (postdoctoral or industry) running and analyzing molecular dynamics simulations of protein–nucleic acid systems. Experience with MD engines (AMBER, GROMACS, NAMD, OpenMM, CHARMM or equivalent) and free-energy methods (FEP, TI, umbrella sampling, metadynamics). Additional skills and preferences Modern RNA and DNA force fields, and parameterization of modified nucleotides or non-canonical backbones. Argonaute biology, RNAi mechanism, or siRNA therapeutic chemistry. Building simulation-ready models from cryo-EM, crystallographic or predicted structures, including flexible regions and missing loops. 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 and reproducible analysis pipelines. Additional information This position is based on site in South San Francisco, California. Regular collaboration with Lilly colleagues in Boston, Indianapolis and San Diego. Lilly is dedicated to helping individuals with disabilities to actively engage in the workforce, ensuring equal opportunities when vying for positions. If you require accommodation to submit a resume for a position at Lilly, please complete the accommodation request form (https://careers.lilly.com/us/en/workplace-accommodation) for further assistance. Please note this is for individuals to request an accommodation as part of the application process and any other correspondence will not receive a response. Lilly is proud to be an EEO Employer and does not discriminate on the basis of age, race, color, religion, gender identity, sex, gender expression, sexual orientation, genetic information, ancestry, national origin, protected veteran status, disability, or any other legally protected status. Our employee resource groups (ERGs) offer strong support networks for their members and are open to all employees. Our current groups include: Africa, Middle East, Central Asia (AMECA), Black Employees at Lilly (BE@Lilly), Chinese Culture Network (CCN), EnAble, Evolve, Lilly Indian Network (LIN), Organization of Latinx at Lilly (OLA), Pride (LGBTQ+ Allies), Veterans Leadership Network (VLN) and Women’s Initiative for Leading at Lilly (WILL). Actual compensation will depend on a candidate’s education, experience, skills, and geographic location. The anticipated wage for this position is $168,000 - $264,000 Full-time equivalent employees also will be eligible for a company bonus (depending, in part, on company and individual performance). In addition, Lilly offers a comprehensive benefit program to eligible employees, including eligibility to participate in a company-sponsored 401(k); pension; vacation benefits; eligibility for medical, dental, vision and prescription drug benefits; flexible benefits (e.g., healthcare and/or dependent day care flexible spending accounts); life insurance and death benefits; certain time off and leave of absence benefits; and well-being benefits (e.g., employee assistance program, fitness benefits, and employee clubs and activities).Lilly reserves the right to amend, modify, or terminate its compensation and benefit programs in its sole discretion and Lilly’s compensation practices and guidelines will apply regarding the details of any promotion or transfer of Lilly employees. #WeAreLilly At Lilly we strive to ensure our employees are part of a team that cares about them and our shared purpose of making life better for those around the world. How do we do this? We continue to look for ways to include, innovate, accelerate and deliver while maintaining integrity, excellence and respect for people. We hope that you seek to join us on our journey as we create medicine and deliver improved outcomes for patients across the globe! #WeAreLilly

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