This initiative calls for fundamentally new approaches in molecular sciences to drive new directions in biotechnology, a critical and emerging technology of the 21st century. This is the second year of a campaign targeting broad annual themes to be pursued through collaborative high risk/high reward projects. This year's solicitation calls for synergistic scientific research collaborations that involve innovative machine learning (ML) methods to foster advances in research on the function of biomolecular systems and have the potential to drive innovation in biotechnology.