Drug-like small molecules that contain azido and akynyl groups are structurally unique because they contain linear angles useful in therapeutics, protein functionalization and biomarking, and in bioconjugation reactions like "click" reactions. The click reaction has proven to be integral in drug design and in research with unnatural amino acids (uAA); however, these technologies rely heavily on molecular modeling. Improving the the accuracy of these models will lead to more accurate simulations and better rational design. The CHARMM force field (FF) is a standard when it comes to all-atom protein and DNA modeling, and since its inception, this FF has been expanded into multiple disciplines. CGenFF is the leading program used to generate CHARMM parameters for "drug-like" molecules that have not been explicitly modeled. However, both these FF lack appropriate parameterization to simulate molecules that contain linear angles within their structure, such as azides and alkynes, and current literature does not contain any solution for modeling these structures. We propose a method to address this issue by (1) developing CHARMM parameters for four small molecules that contain terminal azido and alkynyl groups using the Force Field tool kit (ffTK), (2) addressing linear structure issues seen during ffTK analysis by modifying the procedure so that all CHARMM parameters can be solved, and (3) validating those results via in silico molecular dynamic (MD) simulation. We then combine these parameters with CGenFF to generate parameters for uAA simulation and observe differences between MD simulation and pre-existing crystal structure. In this presentation we describe the process used to obtain the CHARMM parameters with a particular emphasis on determining and validating the dihedral parameters for the linear moieties since these have proven very difficult to parameterize in the past. During validation, we prove that the physics of the linear terminal dihedral angles are well-represented by a large number of parameter sets without compromising molecular structure. Next, we prove the reliability of our parameter set by running MD simulations to prove our modeled structures match those found in literature and quantum theory. Finally, protein MD compares simulation with crystallographic data using a protein that contains an azide uAA. These results provide an unprecedented view into how uAAs influence protein structure.

Azide and alkyne CHARMM parameterization with Unnatural Amino Acid (uAA) protein simulation

2019 Spring National Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.