Explicit Inclusion of Induced Polarization in Atomistic Force Fields Based on the Classical Drude Oscillator Model (2016)

To study energetics and structural transitions at the atomisticlevel in complex biological molecules such as DNA and proteinscomputational modeling represents a powerful and widely usedapproach [1]. Traditional experimental techniques, such as X-raycrystallography and solution NMR, yield insights into these phe-nomena but are plagued by a number of problems associated withcrystallization and resolution issues, as well as accessibility to shortlived high energy states and time domain information [2]. Duringthe past two decades, several all-atom empirical force ﬁelds (FF) forbiologicalmolecules have been developed, including CHARMM [3, 4],AMBER [5], GROMOS [6], and OPLS [7], among others. They provedto be remarkably useful for a range of systems that contain 10,000or more atoms, being computationally cost-eﬀective due to theutilization of simpliﬁed potential energy functions for determinationof the energies and forces acting on such systems. One of themajor limitations of most of the current force ﬁelds associatedwith such simpliﬁcations is the treatment of electrostatics withinthe framework of the ﬁxed-atomic-charge approximation, whereeﬀective charges assigned to particles are independent of a system’sconﬁguration and are adjusted to account for the inﬂuence of in-duced polarization in an average way. Such force ﬁelds are currentlyused for most of biomolecular simulations and commonly termed“additive” indicating they do not account for many-body inducedpolarization eﬀects explicitly. However, for many complex biologicalsystems such as polyanionic DNAor protein immersed in an aqueoussalt environment, whose conformational behavior is determined toa signiﬁcant extent by solvation eﬀects and interactions with thesurrounding ionic atmosphere, the omission of polarization eﬀectsmay preclude a physically correct description of the forces drivingits conformational behavior. Even for small molecules the dipolemoment is known to vary signiﬁcantly when they are transferredfrom the gas to liquid phase. For example, an isolatedwatermoleculehas a dipole moment of 1.85 D [8], while the average moleculardipole is 2.1 D in the water dimer, increasing in larger water clusters[9]. In the condensed phase it reaches a value between 2.4 and 2.6D, as suggested from classical molecular dynamics (MD) simulationsof the dielectric properties [10, 11], and 2.95 D, as obtained fromab initio MD simulations [12-14] and from analysis of experimentaldata [15, 16]. Additionally, our recent computational studies [17,18], as well as studies of others [19], based on polarizable MDsimulations indicate the water dipole moment to be noticeablyperturbed in the vicinity of the charged groups of proteins.Moreover, dipole moments of various chemical groups in proteinsitself, such as peptide backbone and side chains, were shown tobehave quite diﬀerently in polarizable and non-polarizable environ-ments [18, 20]. In particular, MD simulations of a number of fullysolvated proteins utilizing our recently developed CHARMM Drude-2013 polarizable force ﬁeld produce time series for the dipolemoments of side chains of individual residues characterized bysigniﬁcant variability and systematically higher values compared tothe additive results [18]. A similar trend was observed for the dipolemoments of nucleic acid bases from MD simulations of DNA [20].These observations indicate that the variations of the electronicstructure do impact the dynamics of the system and the microscopicforces dictating the structural and dynamical properties.