Buffer Screening of Protein Formulations Using a Coarse-Grained Protocol Based on Medicinal Chemistry Interactions

In drug and vaccine development, the designed protein formulation should be highly stable against the temperature, pH, buffer, excipients, and other environmental settings. Similarly, in a sensing unit, one needs to know how strongly two biomolecules bind to guide the design of the biorecognition unit accordingly. Typically, the community performs a series of experiments to thoroughly examine the parameter space, the so-called design-of-experiment (DoE) method, to identify the optimal formulation conditions. Unfortunately, extensive physical testing entails high costs, repeatability issues, and a lack of in-depth knowledge of the underlying mechanisms that affect the final outcome. To address these challenges, we developed a physics-based simulation protocol for buffer screening of protein formulations. We are introducing a coarse-grained molecular simulation protocol that consists of six different interactions. The so-called medicinal chemistry interactions (electrostatics, hydrophobicity, hydrogen bonding propensity, disulfide bonding, and water-water) are based on the physical nature of the protein's amino acid and the partitioning/polarity of any other chemical constituent. The protocol is applied in immunoglobulin-based monoclonal antibodies. We have analyzed the protein behavior as a function of acidity (pH) to discover the isoelectric point by solving the Poisson-Boltzmann equation in a mesoscale grid. To identify the conditions under which the protein oligomerizes in a given buffer, pH, temperature, and ionic strength, we are performing dissipative particle dynamics (DPD) simulations. The protocol allows researchers to reach the high time/space scales required to study protein formulations in their full complexity. Combined with the disruptive protein folding artificial intelligence (AI) algorithms that have been recently developed, the protocol creates a powerful digital framework for cultivating advanced pharmaceutical and biological applications.