An exact expression to calculate the derivatives of position-dependent observables in molecular simulations with flexible constraints

TL;DR

This paper introduces an exact, parameter-free algorithm for computing derivatives of position-dependent observables in molecular systems with flexible constraints, validated on biologically relevant molecules.

Contribution

It presents the first exact method for derivatives in systems with flexible constraints, requiring only Hessian sub-block inversion, improving accuracy over finite differences.

Findings

The method is exact and parameter-free.

Validated on methanol, N-methyl-acetamide, and tri-glycine.

Outperforms finite-difference approaches.

Abstract

In this work, we introduce an algorithm to compute the derivatives of physical observables along the constrained subspace when flexible constraints are imposed on the system (i.e., constraints in which the hard coordinates are fixed to configuration-dependent values). The presented scheme is exact, it does not contain any tunable parameter, and it only requires the calculation and inversion of a sub-block of the Hessian matrix of second derivatives of the function through which the constraints are defined. We also present a practical application to the case in which the sought observables are the Euclidean coordinates of complex molecular systems, and the function whose minimization defines the constraints is the potential energy. Finally, and in order to validate the method, which, as far as we are aware, is the first of its kind in the literature, we compare it to the natural and straightforward finite-differences approach in three molecules of biological relevance: methanol, N-methyl-acetamide and a tri-glycine peptide