Table 2.

Improving HREX-SRTI Efficiency for the L99A T4 Lysozyme Mutant in Complex with Indole

System	NSRTI	p	α	ΔGPrt(SD), kcal/mol	NHREX	Accept, %
V87p-A:V111p-A:L118p-A
SRTI	12	2	1.5	34.2(3.8)	-	-
SRTI	23	2	1.5	36.9(3.3)	-	-
HREX-SRTI	23	2	1.5	39.5(1.4)	1000a	30
HREX-SRTI	12	1	0.3	29.4(0.9)	2000	17
HREX-SRTI	12	1	0.4	30.6(0.8)	2000	13
HREX-SRTI	12	1	0.5	33.6(1.2)	2000	9
V111p-A
SRTI	12	2	1.5	−0.6(1.8)	-	-
HREX-SRTI	12	2	1.5	−1.0(1.8)	2000	19
HREX-SRTI	23	2	1.5	−1.6(0.5)	2000	48
HREX-SRTI	12	1	0.4	−1.7(0.2)	2000	29

These results are representative of the protein leg of the thermodynamic cycle (Figure 1) using RESP@HF/6-31G(d) point charges on the ligand. N_SRTI, and N_HREX refer to the number of TI windows and exchange cycles, respectively. Soft-core parameters involved in optimization are p and α (see text for description). Averages and standard deviations (SD) are over 8 independent simulations with distinct starting positions of the ligand in the binding site. Two unphysical references, namely V87p-A:V111p-A:L118p-A and V111p-A are considered. By design, the use of the former reference with HREX should enhance sidechain torsions of the V87, V111 and L118 along with rotation and flipping of the ligand. The latter reference should enhance torsions of the V111 sidechain and rotations of the ligand. Unless otherwise stated, all TI windows were run in NPT ensemble at 1 atm and 300 K for 4 ns.

^aEach window was run for 2 ns.