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Abstract

Van der Waals (vdW) interactions are ubiquitous in molecules
and condensed matter, and play a crucial role in determining the
structure, stability, and function for a wide variety of systems. The
accurate prediction of these interactions from first principles is a
substantial challenge because they are inherently quantum mechanical
phenomena that arise from correlations between many
electrons within a given molecular system. We introduce an efficient
method that accurately describes the nonadditive many-body
vdW energy contributions arising from interactions that cannot be
modeled by an effective pairwise approach, and demonstrate that
such contributions can significantly exceed the energy of thermal
fluctuations—a critical accuracy threshold highly coveted during
molecular simulations—in the prediction of several relevant properties.
Cases studied include the binding affinity of ellipticine, a DNAintercalating
anticancer agent, the relative energetics between the
A- and B-conformations of DNA, and the thermodynamic stability
among competing paracetamol molecular crystal polymorphs. Our
findings suggest that inclusion of the many-body vdW energy is
essential for achieving chemical accuracy and therefore must be
accounted for in molecular simulations.