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bioRxiv · 10.1101/2021.02.17.431654

Weighted force analysis method for derivation of multidimensional free energy landscapes from adaptively-biased replica simulations

Marinelli, F.·Faraldo-Gomez, J.
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Abstract

A methodology is proposed for the calculation of multidimensional free-energy landscapes of molecular systems, based on analysis of multiple Molecular Dynamics trajectories wherein adaptive biases have been applied to enhance the sampling of different collective variables. In this approach, which we refer to as Force Correction Analysis Method (FCAM), local averages of the total and biasing forces are evaluated post-hoc, and the latter are subtracted from the former to obtain unbiased estimates of the mean force across collective-variable space. Multidimensional free-energy surfaces and minimum free-energy pathways are then derived from integration of the mean force landscape through kinetic Monte Carlo algorithm. To evaluate the proposed method, a series of numerical tests and comparisons with existing approaches were carried out for small molecules, peptides, and proteins, based on all-atom trajectories generated with standard, concurrent and replica-exchange Metadynamics in collective-variable spaces ranging from one- to six-dimensional. The tests confirm the correctness of the FCAM formulation and demonstrate that calculated mean forces and free energies converge rapidly and accurately, outperforming other methods used to unbias this kind of simulation data. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=102 SRC="FIGDIR/small/431654v5_ufig1.gif" ALT="Figure 1"> View larger version (45K): org.highwire.dtl.DTLVardef@1412289org.highwire.dtl.DTLVardef@1425d53org.highwire.dtl.DTLVardef@1fcf5d0org.highwire.dtl.DTLVardef@6e6941_HPS_FORMAT_FIGEXP M_FIG TOC/Abstract Graphic C_FIG

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Marinelli, F., Faraldo-Gomez, J.. 2021-02-18. Weighted force analysis method for derivation of multidimensional free energy landscapes from adaptively-biased replica simulations. https://doi.org/10.1101/2021.02.17.431654

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