SBIR-STTR Award

In this SBIR project, Schrodinger, Inc. will develop a novel force field for peptides and proteins that will include parameters for new simulation algorithms and will incorporate the force field into a molecular modeling program. The resulting molecular mechanics simulation package will include an accurate description of polarizability and solvent effects at minimal computational cost, meeting a major longstanding goal of biomolecular modeling. To achieve this goal, Schrodinger researchers and their collaborators will use Schrodinger's fast local MP2 algorithms to generate parameters for a new, efficient fluctuating charge method and will implement the fluctuating charge method in the molecular simulation program IMPACT. Schrodinger's efficient Poisson-Boltzmann solver will also be integrated with the new software, allowing rapid evaluation of solvent effects during classical simulations. In Phase I, Schrodinger will develop a preliminary version of the software, compute the necessary parameters for peptides, and perform test calculations on small peptides in solution to validate the methods used by comparing the molecular mechanics results with accurate quantum mechanics. Phase II work will include tests of the software's ability to predict peptide structures in solution and optimization of the numerical algorithms to obtain reasonable performance for protein simulations and free energy perturbation calculations.Proposed commercial application:Software capable of accurate classical simulations of peptides and proteins would have huge commercial potential in the drug industry, considerably enhancing the impact of molecular modeling on drug design. The Phase Il tests described above would generate immediate commercial interest in this software package.National Institute fo General Medical Sciences (NIGMS)

Schrodinger, Inc. proposes to continue developing a novel polarizable force field for proteins and peptides based upon a fluctuating charge (FQ) and dipole model. The force field will include polarizability and solvent effects at a minimal computational cost. Phase I preliminary results show that the FQ model can be fit directly to quantum chemical data for peptides and that the resulting model provides an excellent reproduction of quantum chemical many body energetics of polypeptides. In Phase II, Schrodinger will first use the FQ model to construct a full polarizable force field by constructing a transferable functional form for the electrostatics and then adding van der Waals and valence terms. Secondly, Schrodinger will develop both explicit water and continuum dielectric models of aqueous solvation so that the modeling with the polarizable force field can be carried out in the actual biological environment. The polarizable force field and solvation models will be implemented in a robust molecular modeling code with fast simulation algorithms. Lastly, the force field and simulation algorithms will be rigorously tested to validate that they provide significant improvements over existing fixed charge force fields.

Thesaurus Terms:
biomedical equipment, biomedical equipment development, dipole moment, peptide, protein chemical model, dielectric property, intermolecular interaction, ionic bond, solvent, water quantum chemistry