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The difficulties encountered in sampling of systems with rough energy landscapes using present methodology significantly limit the impact of simulation on molecular biology, in particular protein folding and design. Here, we present a major methodological development based on a promising new technique, the reference potential spatial warping algorithm (REPSWA) [Z. Zhu et al., Phys. Rev. Lett., 88 (2002), pp. 100201–100204], and present applications to several realistic systems. REPSWA works by introducing a variable transformation in the classical partition function that reduces the volume of phase space associated with a priori known barrier regions while increasing that associated with attractive basins. In this way, the partition function is preserved so that enhanced sampling is achieved without the need for reweighting phase-space averages. Here, a new class of transformations, designed to overcome the barriers induced by intermolecular/nonbonded interactions, whose locations are not known a priori, is introduced. The new transformations are designed to work in synergy with transformations originally introduced for overcoming intramolecular barriers. The new transformation adapts to the fluctuating local environment and is able to handle barriers that arise “on the fly.” Thus, the new method is referred to as dynamic contact REPSWA (DC-REPSWA). In addition, combining hybrid Monte Carlo (HMC) with DC-REPSWA allows more aggressive sampling to take place. The combined DC-REPSWA-HMC method and its variants are shown to substantially enhance conformational sampling in long molecular chains composed of interacting single beads and beads with branches. The latter topologies characterize the united residue and united side chain representation of protein structures.