Probabilistic model to treat flexibility in molecular contacts

Evaluating accessible conformational space is computationally expensive and thermal motions are partly neglected in computer models of molecular interactions. This produces error into the estimates of binding strength. We introduce a method for modelling interactions so that structural flexibility is inherently taken into account. It has a statistical model for three-dimensional (3D) properties of non-local contacts and a physics-based description of local interactions, based on mechanical torque. The form of the torque barrier is derived using a representation of the local electronic structure, which is presumed to improve transferability, compared to traditional force fields. The non-local contacts are more distant than 1–4 interactions and target atoms are represented by 3D probability densities. Probability mass quantifies the strength of contact and is calculated as an overlap integral. Repulsion is described by negative probability density, allowing probability mass to be used as the descriptor of contact preference. As a result, we are able to transform the high-dimensional problem into a simpler evaluation of 3D integrals. We outline how this scoring function gives a tool to study the enthalpy–entropy compensation and demonstrate the feasibility of our approach by evaluating numerical probability masses for chosen side chain to main chain contacts in a lysine dipeptide structure.