Prediction of cyclohexane-water distribution coefficients for the SAMPL5 data set using molecular dynamics simulations with the OPLS-AA force field

International audienceAll-atom molecular dynamics (MD) simulations were used to predict water-cyclohexane distribution coefficients D cw of a range of small molecules as part of the SAMPL5 blind prediction challenge. Molecules were parameterized with the trans-ferable all-atom OPLS-AA force field, which required the derivation of new parameters for sulfamides and heterocycles and validation of cyclohexane parameters as a solvent. The distribution coefficient was calculated from the solvation free energies of the compound in water and cyclohexane. Absolute solvation free energies were computed by an established protocol using windowed alchemical free energy perturbation with thermodynamic integration. This protocol resulted in an overall root mean square error (RMSE) in log D cw of almost 4 log units and an overall signed error of −3 compared to experimental data. There was no substantial overall difference in accuracy between simulating in NV T and NPT ensembles. The signed error suggests a systematic error but the experimental D cw data on their own are insufficient to Manuscript Click here to download Manuscript sampl5-manuscript.pdf Click here to view linked References 2 Ian M. Kenney et al. uncover the source of this error. Preliminary work suggests that the major source of error lies in the hydration free energy calculations

Absolute binding enthalpy calculations using molecular dynamics simulations

Computers play an essential role in drug discovery as advancements in technology, hardware, and algorithms have allowed for improved simulations of biomolecules. The field of drug discovery stands to benefit significantly from these developments. Currently, many innovative approaches to studying drug binding and predicting binding affinity are being explored. Using computational methods to predict thermodynamic components in drug design has become routine. While progress has been made in calculating free energy, the prediction of enthalpy and entropy remains an area that requires further investigation. These components reflect the interactions and dynamics between the ligand and protein. However, despite years of research, our understanding of these components still needs to be improved. Computing the enthalpy is particularly challenging, and even the achievable accuracy of these predictions is still not precise despite the apparent simplicity of the calculations per se. In my thesis, I conduct a series of studies to examine the potential utility of absolute binding enthalpy calculations using the direct method based on molecular dynamics simulations. In Chapter 3, I first assess the accuracy of water models and the host-guest force field in calculating the absolute binding enthalpy for 25 host-guest pairs. While actual protein-ligand or protein-protein data would be ideal for evaluating force fields, using very simplified test systems can be helpful for preliminary exploration of parameters. Then, in Chapter 4, I focus on predicting the binding enthalpies of small molecules to bromodomains, which are small protein modules involved in gene regulation linked to many diseases, such as cancer and inflammation. I evaluated the direct method for calculating absolute binding enthalpies by testing its ability to predict the binding enthalpies of 10 different ligands to BRD4-1. The results showed a strong correlation between the behaviour of the ZA loop and the predicted enthalpy. In Chapter 5, I extended the study by evaluating the method to include multiple protein-protein complexes essential in all cellular processes, ranging from signal transmission to enzyme activity. Understanding the thermodynamics of protein-peptide binding events is a significant challenge in computational chemistry. The complexity of both components having many degrees of freedom presents a substantial challenge for methods attempting to directly compute the enthalpic contribution to binding. Despite this, the method produced highly accurate and well-converged binding enthalpies for small protein-protein systems. Perhaps unsurprisingly, most inaccuracies can be attributed to poor conformational sampling. Nevertheless, I have shown that this can actually be used to highlight the possibility of hidden states. Overall, my work has shown that absolute enthalpy calculations using the direct method can be performed on protein-ligand and protein-protein systems with reasonable accuracy and that this is a useful contribution to computational drug design